Methods for modifying RNA splicing
11608501 · 2023-03-21
Assignee
Inventors
- Anuradha Bhattacharyya (Edison, NJ)
- Amal Dakka (Whitehouse Station, NJ)
- Kerstin Effenberger (Metuchen, NJ, US)
- Vijayalakshmi Gabbeta (Bridgewater, NJ, US)
- Minakshi B. Jani (Iselin, NJ, US)
- Wencheng Li (Martinsville, NJ, US)
- Nikolai Naryshkin (East Brunswick, NJ)
- Christopher Trotta (Somerset, NJ)
- Kari Wiedinger (New Providence, NJ, US)
Cpc classification
C12N15/111
CHEMISTRY; METALLURGY
A61K31/501
HUMAN NECESSITIES
A61K31/454
HUMAN NECESSITIES
C12N15/63
CHEMISTRY; METALLURGY
International classification
C12N15/11
CHEMISTRY; METALLURGY
Abstract
Described herein is an intronic recognition element for splicing modifier (iREMS) that can be recognized by a small molecule splicing modifier compound of Formula (I) provided herein or a form thereof, wherein W, X, A and B are as defined herein. In one aspect, methods for modifying RNA splicing to modulate the amount of a product of a gene, wherein a precursor RNA transcript transcribed from the gene that contains an intronic REMS is modified utilizing a splicing modifier compound of Formula (I), are described herein. In another aspect, methods for modifying RNA splicing to modulate the amount of an RNA transcript or protein product encoded by a gene, wherein a precursor RNA transcript transcribed from the gene is modified to comprise an intronic REMS utilizing a splicing modifier compound of Formula (I), are described herein.
Claims
1. A method for modifying RNA splicing in order to produce a mature mRNA transcript having an intronic exon (iExon), the method comprising contacting 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol having the formula ##STR00183## or a form thereof with a cell containing a pre-mRNA transcript in cell culture or with a cell lysate containing a pre-mRNA transcript, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: (a) ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR-0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; (b) ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CENPI, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CRYBG3, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DENND1A, DENND4A, DENND5A, DET1, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, ERC2, EVC, FAM162A, FAM174A, FAM195B, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GLCE, GOLGB1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR-0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, 44628, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, MYLK, NLGN1, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RASIP1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, STXBP4, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TEKT4P2, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25, or (c) ABHD10, ADAM17, AGPAT4, AGPS, AKT1, ANKRD13C, ANXA11, APIP, APPL2, ARHGAP1, ARHGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD10, C10orf76, C11orf30, C11orf73, C12orf4, C1orf27, C1QTNF9B-AS1, CCNL2, CDH18, CENPI, CEP57, CMSS1, CNOT7, COPS7B, CRISPLD2, CUX1, DCAF17, DDX42, DENND4A, DENND5A, DET1, DLG5, DMXL1, DNAJA4, DNMBP, ENAH, EP300, ERC1, EVC, EXOC3, EXOC6B, FAM162A, FAM174A, FAM208B, FAM49B, FBN2, GBP1, GNG12, GXYLT1, HDX, HMGXB4, HOXB3, HSD17B4, IFT57, IKBKAP, INO80, INPP4B, ITCH, IVD, KDM6A, KDSR, KIAA1524, KIAA1715, KIDINS220, L3MBTL2, LGALS3, LOC400927, LRRC42, LYRM1, MACROD2, MANEA, MARCH7, MARCH8, MEAF6, MEMO1, MFN2, MMS19, MORF4L1, MRPL39, MRPL45, MRPS28, MYCBP2, MYLK, MZT1, NEDD4, NFASC, NGF, NIPA1, NLN, NREP, NUPL1, OSBPL3, PAPD4, PBX3, PDE7A, PIGN, PITPNB, PNISR, POMT2, PPARG, PPFIBP1, PRPF31, PSMA4, PXK, RAB23, RAF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA2, SPIDR, SSBP1, STRADB, STXBP6, SUPT20H, TAF2, TASP1, TBCA, TBL1XR1, TCF4, TJAP1, TJP2, TMEM214, TMX3, TNRC6A, TXNL4B, UBE2D3, UBE2L3, UNC13B, URGCP-MRPS24, VDAC2, WHSC2, WNK1, XRN2, ZFP82, ZNF138, ZNF350, ZNF37BP, ZNF618, ZNF680, ZNF777, ZNF804A, and ZSCAN25.
2. A method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced from a pre-mRNA transcript, the method comprising contacting 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol having the formula ##STR00184## or a form thereof with a cell containing a pre-mRNA transcript in cell culture or with a cell lysate containing a pre-mRNA transcript, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: an intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: (a) ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DET1, DENND1A, DENND4A, DENND5A, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EVC, FAM162A, FAM174A, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR-0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, MARCH8, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RCOR3, RERE, RNF130, RNF144A, RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25, (b) ADAL, ADAM23, ADAMTS19, AGPS, AKAP8L, ANKRD13C, ANXA11, ARL15, ARSJ, BECN1, BIN3, BTBD10, C11orf30, C12orf4, C1orf27, C2orf47, CACNB1, CACNB4, CADM2, CDH18, CENPI, CEP162, CEP170, CEP192, CHEK1, CHRM2, CMAHP, CNRIP1, CNTN1, CRYBG3, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DENND1A, DENND4A, DENND5A, DET1, DGKI, DHFR, DIAPH3, DLG5, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, ERC2, EVC, FAM162A, FAM174A, FAM195B, FAM208B, FAM69B, FBXL16, FGD4, FHOD3, GALC, GLCE, GOLGB1, GXYLT1, HDAC5, HDX, HTT, IFT57, INO80, INVS, KDM6A, KIDINS220, KIF21A, L3MBTL2, LINCR-0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MAPK10, 44628, MDN1, MEAF6, MEMO1, MFN2, MLLT10, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, MYLK, NLGN1, NSUN4, NUPL1, OSBPL3, PAPD4, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PITPNB, PMS1, POMT2, PSMA4, RAB23, RAF1, RASIP1, RCOR3, RERE, RNF130 RNF144A RNF213, RPF2, RPS10, SCO1, SENP6, SF3B3, SGMS1, SGPL1, SLC25A16, SLC25A17, SNX24, SNX7, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRADB, STXBP4, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TCF4, TEKT4P2, TET1, TIAM1, TJP2, TMEM214, TNRC6A, TRAF3, TRIM65, TSPAN7, UBN2, URGCP-MRPS24, UVRAG, WDR27, WDR90, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF836, and ZSCAN25; or (c) ABHD10, ADAM17, AGPAT4, AGPS, AKT1, ANKRD13C, ANXA11, APIP, APPL2, ARHGAP1, ARHGAP5, ARL15, ARL5B, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD10, C10orf76, C11orf30, C11orf73, C12orf4, C1orf27, C1QTNF9B-AS1, CCNL2, CDH18, CENPI, CEP57, CMSS1, CNOT7, COPS7B, CRISPLD2, CUX1, DCAF17, DDX42, DENND4A, DENND5A, DET1, DLG5, DMXL1, DNAJA4, DNMBP, ENAH, EP300, ERC1, EVC, EXOC3, EXOC6B, FAM162A, FAM174A, FAM208B, FAM49B, FBN2, GBP1, GNG12, GXYLT1, HDX, HMGXB4, HOXB3, HSD17B4, IFT57, IKBKAP, INO80, INPP4B, ITCH, IVD, KDM6A, KDSR, KIAA1524, KIAA1715, KIDINS220, L3MBTL2, LGALS3, LOC400927, LRRC42, LYRM1, MACROD2, MANEA, MARCH7, MARCH8, MEAF6, MEMO1, MFN2, MMS19, MORF4L1, MRPL39, MRPL45, MRPS28, MYCBP2, MYLK, MZT1, NEDD4, NFASC, NGF, NIPA1, NLN, NREP, NUPL1, OSBPL3, PAPD4, PBX3, PDE7A, PIGN, PITPNB, PNISR, POMT2, PPARG, PPFIBP1, PRPF31, PSMA4, PXK, RAB23, RAF1, RAPGEF1, RBBP8, RERE, RGL1, RPF2, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SH2B3, SKP1, SLC12A2, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA2, SPIDR, SSBP1, STRADB, STXBP6, SUPT20H, TAF2, TASP1, TBCA, TBL1XR1, TCF4, TJAP1, TJP2, TMEM214, TMX3, TNRC6A, TXNL4B, UBE2D3, UBE2L3, UNC13B, URGCP-MRPS24, VDAC2, WHSC2, WNK1, XRN2, ZFP82, ZNF138, ZNF350, ZNF37BP, ZNF618, ZNF680, ZNF777, ZNF804A, and ZSCAN25.
3. The method of claim 1, wherein the iREMS comprises an RNA sequence GAguragu, and wherein r is adenine or guanine.
4. The method of claim 1, wherein the iREMS comprises an RNA sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide, and wherein the RNA sequence NNGAgurngn (SEQ ID NO: 1) is selected from the group consisting of ANGAgurngn (SEQ ID NO: 4), CNGAgurngn (SEQ ID NO: 5), GNGAgurngn (SEQ ID NO: 6), UNGAgurngn (SEQ ID NO: 7), NAGAgurngn (SEQ ID NO: 8), NCGAgurngn (SEQ ID NO: 9), NGGAgurngn (SEQ ID NO: 10), NUGAgurngn (SEQ ID NO: 11), AAGAgurngn (SEQ ID NO: 12), ACGAgurngn (SEQ ID NO: 13), AGGAgurngn (SEQ ID NO: 14), AUGAgurngn (SEQ ID NO: 15), CAGAgurngn (SEQ ID NO: 16), CCGAgurngn (SEQ ID NO: 17), CGGAgurngn (SEQ ID NO: 18), CUGAgurngn (SEQ ID NO: 19), GAGAgurngn (SEQ ID NO: 20), GCGAgurngn (SEQ ID NO: 21), GGGAgurngn (SEQ ID NO: 22), GUGAgurngn (SEQ ID NO: 23), UAGAgurngn (SEQ ID NO: 24), UCGAgurngn (SEQ ID NO: 25), UGGAgurngn (SEQ ID NO: 52), and UUGAgurngn (SEQ ID NO: 53), wherein r is adenine or guanine and n or N is any nucleotide.
5. The method of claim 1, wherein the iREMS comprises an RNA sequence NNGAguragu (SEQ ID NO: 2), wherein r is adenine or guanine and N is any nucleotide, and wherein the RNA sequence NNGAguragu (SEQ ID NO: 2) is selected from the group consisting of ANGAguragu (SEQ ID NO: 28), CNGAguragu (SEQ ID NO: 29), GNGAguragu (SEQ ID NO: 30), UNGAguragu (SEQ ID NO: 31), NAGAguragu (SEQ ID NO: 32), NCGAguragu (SEQ ID NO: 33), NGGAguragu (SEQ ID NO: 34), NUGAguragu (SEQ ID NO: 35), AAGAguragu (SEQ ID NO: 36), ACGAguragu (SEQ ID NO: 37), AGGAguragu (SEQ ID NO: 38), AUGAguragu (SEQ ID NO: 39), CAGAguragu (SEQ ID NO: 40), CCGAguragu (SEQ ID NO: 41), CGGAguragu (SEQ ID NO: 42), CUGAguragu (SEQ ID NO: 43), GAGAguragu (SEQ ID NO: 44), GCGAguragu (SEQ ID NO: 45), GGGAguragu (SEQ ID NO: 46), GUGAguragu (SEQ ID NO: 47), UAGAguragu (SEQ ID NO: 48), UCGAguragu (SEQ ID NO: 49), UGGAguragu (SEQ ID NO: 489) and UUGAguragu (SEQ ID NO: 508), wherein r is adenine or guanine, and N is any nucleotide.
6. The method of claim 2, wherein the iREMS comprises an RNA sequence GAguragu, and wherein r is adenine or guanine.
7. The method of claim 2, wherein the iREMS comprises an RNA sequence NNGAgurngn (SEQ ID NO: 1), wherein r is adenine or guanine and n or N is any nucleotide, and wherein the RNA sequence NNGAgurngn (SEQ ID NO: 1) is selected from the group consisting of ANGAgurngn (SEQ ID NO: 4), CNGAgurngn (SEQ ID NO: 5), GNGAgurngn (SEQ ID NO: 6), UNGAgurngn (SEQ ID NO: 7), NAGAgurngn (SEQ ID NO: 8), NCGAgurngn (SEQ ID NO: 9), NGGAgurngn (SEQ ID NO: 10), NUGAgurngn (SEQ ID NO: 11), AAGAgurngn (SEQ ID NO: 12), ACGAgurngn (SEQ ID NO: 13), AGGAgurngn (SEQ ID NO: 14), AUGAgurngn (SEQ ID NO: 15), CAGAgurngn (SEQ ID NO: 16), CCGAgurngn (SEQ ID NO: 17), CGGAgurngn (SEQ ID NO: 18), CUGAgurngn (SEQ ID NO: 19), GAGAgurngn (SEQ ID NO: 20), GCGAgurngn (SEQ ID NO: 21), GGGAgurngn (SEQ ID NO: 22), GUGAgurngn (SEQ ID NO: 23), UAGAgurngn (SEQ ID NO: 24), UCGAgurngn (SEQ ID NO: 25), UGGAgurngn (SEQ ID NO: 52), and UUGAgurngn (SEQ ID NO: 53), wherein r is adenine or guanine and n or N is any nucleotide.
8. The method of claim 2, wherein the iREMS comprises an RNA sequence NNGAguragu (SEQ ID NO: 2), wherein r is adenine or guanine and N is any nucleotide, and wherein the RNA sequence NNGAguragu (SEQ ID NO: 2) is selected from the group consisting of ANGAguragu (SEQ ID NO: 28), CNGAguragu (SEQ ID NO: 29), GNGAguragu (SEQ ID NO: 30), UNGAguragu (SEQ ID NO: 31), NAGAguragu (SEQ ID NO: 32), NCGAguragu (SEQ ID NO: 33), NGGAguragu (SEQ ID NO: 34), NUGAguragu (SEQ ID NO: 35), AAGAguragu (SEQ ID NO: 36), ACGAguragu (SEQ ID NO: 37), AGGAguragu (SEQ ID NO: 38), AUGAguragu (SEQ ID NO: 39), CAGAguragu (SEQ ID NO: 40), CCGAguragu (SEQ ID NO: 41), CGGAguragu (SEQ ID NO: 42), CUGAguragu (SEQ ID NO: 43), GAGAguragu (SEQ ID NO: 44), GCGAguragu (SEQ ID NO: 45), GGGAguragu (SEQ ID NO: 46), GUGAguragu (SEQ ID NO: 47), UAGAguragu (SEQ ID NO: 48), UCGAguragu (SEQ ID NO: 49), UGGAguragu (SEQ ID NO: 489) and UUGAguragu (SEQ ID NO: 508), wherein r is adenine or guanine, and N is any nucleotide.
9. The method of claim 1, wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: (a) C12orf4, CDH18, CHEK1, DHFR, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, POMT2, TAF2, TRIM65, and WDR27; (b) ADAMTS19, BECN1, CACNB4, CADM2, CHEK1, CHRM2, CMAHP, DENND4A, DHFR, EVC, GXYLT1, MEMO1, MYCBP2, NUPL1, PDXDC1, SENP6, SPIDR, TNRC6A, TRIM65, URGCP-MRPS24, WDR90, ZFP82, ZNF618, and ZNF680; or (c) AGPS, AKT1, ANXA11, ARHGAP5, ARL15, ATF6, BIN3, C11orf30, C11orf73, CDH18, CENPI, DCAF17, DENND4A, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1715, KIDINS220, MYCBP2, SLC25A17, SNX24, SNX7, SPIDR, STRADB, TASP1, TCF4, TMEM214, UBE2D3, XRN2, ZNF618, and ZNF777.
10. The method of claim 1, wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: (a) ARL15, PDXDC2P, and ZNF37BP; (b) ERC2, FHOD3, HDX, HTT, KDM6A, LOC400927, LRRC42, MACROD2, MEAF6, PAPD4, PDE7A, TAF2, TET1, TIAM1, and WDR27; or (c) BECN1, BHMT2, C1orf27, ENAH, KIAA1524, LOC400927, LRRC42, LYRM1, MFN2, MORF4L1, NGF, NUPL1, PAPD4, PDE7A, RERE, SF3B3, STXBP6, TAF2, URGCP-MRPS24, WNK1, ZNF350, and ZNF680.
11. The method of claim 1, wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: (a) ELMO2; (b) ARL15, C12orf4, CDH18, ELMO2, PDXDC2P, POMT2, RASIP1, and ZNF37BP; or (c) ARL15, ASAP1, C12orf4, EVC, GXYLT1, HDX, KDM6A, MACROD2, MEAF6, MEMO1, POMT2, SENP6, TBCA, TNRC6A, UBE2L3, VDAC2, ZFP82, ZNF138, and ZNF37BP.
12. The method of claim 1, wherein: (a) the pre-mRNA transcript is a pre-mRNA transcript of the HTT gene; (b) the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: ARL15, C12orf4, CDH18, CHEK1, DHFR, ELMO2, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, PDXDC2P, POMT2, TAF2, TRIM65, WDR27, ZNF37BP, ADAMTS19, BECN1, CACNB4, CADM2, CHRM2, CMAHP, DENND4A, ERC2, EVC, FHOD3, GXYLT1, HTT, KDM6A, MACROD2, MEMO1, NUPL1, PDXDC1, RASIP1, SENP6, SPIDR, TET1, TIAM1, TNRC6A, URGCP-MRPS24, WDR90, ZFP82, ZNF618, ZNF680, AGPS, AKT1, ANXA11, ARHGAP5, ATF6, ASAP1, BHMT2, BIN3, C11orf30, C11orf73, C1orf27, CENP1, DCAF17, ENAH, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1524, KIAA1715, KIDINS220, LYRM1, MFN2, MORF4L1, NGF, RERE, SF3B3, SLC25A17, SNX24, SNX7, STRADB, STXBP6, TA5P1, TBCA, TCF4, TMEM214, UBE2D3, UBE2L3, VDAC2, WNK1, XRN2, ZNF138, ZNF350, and ZNF777; or (c) the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of DIAPH3, NIPA1, RAF1, DCAF17 2a, GNG12, HMGXB4, MRPL45, NSUN4, PITPNB, DCAF17 6a, DMXL1, GALC, GBP1, SREK1, SSBP1, DENND5A, DGK1, GTSF1, L3MBTL2, MMS19, PMS1, PRPF31, SKP1, and SUPT20H.
13. The method of claim 2, wherein the intron further comprises in 5′ to 3′ order: a 5′ splice site, a branch point, and a 3′ splice site, wherein the 5′ splice site, the branch point, and the 3′ splice site are upstream of the iREMS.
14. The method of claim 2, wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: (a) C12orf4, CDH18, CHEK1, DHFR, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, POMT2, TAF2, TRIM65, and WDR27; (b) ADAMTS19, BECN1, CACNB4, CADM2, CHEK1, CHRM2, CMAHP, DENND4A, DHFR, EVC, GXYLT1, MEMO1, MYCBP2, NUPL1, PDXDC1, SENP6, SPIDR, TNRC6A, TRIM65, URGCP-MRPS24, WDR90, ZFP82, ZNF618, and ZNF680; or (c) AGPS, AKT1, ANXA11, ARHGAP5, ARL15, ATF6, BIN3, C11orf30, C11orf73, CDH18, CENPI, DCAF17, DENND4A, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1715, KIDINS220, MYCBP2, SLC25A17, SNX24, SNX7, SPIDR, STRADB, TASP1, TCF4, TMEM214, UBE2D3, XRN2, ZNF618, and ZNF777.
15. The method of claim 2, wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: (a) ARL15, PDXDC2P, and ZNF37BP; (b) ERC2, FHOD3, HDX, HTT, KDM6A, LOC400927, LRRC42, MACROD2, MEAF6, PAPD4, PDE7A, TAF2, TET1, TIAM1, and WDR27; or (c) BECN1, BHMT2, C1orf27, ENAH, KIAA1524, LOC400927, LRRC42, LYRM1, MFN2, MORF4L1, NGF, NUPL1, PAPD4, PDE7A, RERE, SF3B3, STXBP6, TAF2, URGCP-MRPS24, WNK1, ZNF350, and ZNF680.
16. The method of claim 2, wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: (a) ELMO2; (b) ARL15, C12orf4, CDH18, ELMO2, PDXDC2P, POMT2, RASIP1, and ZNF37BP; or (c) ARL15, ASAP1, C12orf4, EVC, GXYLT1, HDX, KDM6A, MACROD2, MEAF6, MEMO1, POMT2, SENP6, TBCA, TNRC6A, UBE2L3, VDAC2, ZFP82, ZNF138, and ZNF37BP.
17. The method of claim 2, wherein: (a) the pre-mRNA transcript is a pre-mRNA transcript of the HTT gene; (b) the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of: ARL15, C12orf4, CDH18, CHEK1, DHFR, ELMO2, HDX, LOC400927, LRRC42, MEAF6, MYCBP2, PAPD4, PDE7A, PDXDC2P, POMT2, TAF2, TRIM65, WDR27, ZNF37BP, ADAMTS19, BECN1, CACNB4, CADM2, CHRM2, CMAHP, DENND4A, ERC2, EVC, FHOD3, GXYLT1, HTT, KDM6A, MACROD2, MEMO1, NUPL1, PDXDC1, RASIP1, SENP6, SPIDR, TET1, TIAM1, TNRC6A, URGCP-MRPS24, WDR90, ZFP82, ZNF618, ZNF680, AGPS, AKT1, ANXA11, ARHGAP5, ATF6, ASAP1, BHMT2, BIN3, C11orf30, C11orf73, C1orf27, CENP1, DCAF17, ENAH, EXOC6B, FAM162A, FAM174A, FAM208B, HOXB3, IFT57, IVD, KIAA1524, KIAA1715, KIDINS220, LYRM1, MFN2, MORF4L1, NGF, RERE, SF3B3, SLC25A17, SNX24, SNX7, STRADB, STXBP6, TASP1, TBCA, TCF4, TMEM214, UBE2D3, UBE2L3, VDAC2, WNK1, XRN2, ZNF138, ZNF350, and ZNF777; or (c) the pre-mRNA transcript is a pre-mRNA transcript of a gene selected from the group consisting of DIAPH3, NIPA1, RAF1, DCAF17 2a, GNG12, HMGXB4, MRPL45, NSUN4, PITPNB, DCAF17 6a, DMXL1, GALC, GBP1, SREK1, SSBP1, DENND5A, DGK1, GTSF1, L3MBTL2, MMS19, PMS1, PRPF31, SKP1, and SUPT20H.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1)
(2)
(3)
INTRONIC RECOGNITION ELEMENTS FOR SPLICING MODIFIER (iREMS)
(4) In one aspect, provided herein is an intronic recognition element for splicing modifier (otherwise referred to as “iREMS”) having elements capable of being recognized by a small molecule splicing modifier, whereby the elements of the associated iREMS complex, in combination with the small molecule splicing modifier, affect interactions with the spliceosome as further described herein. In a specific aspect, the intronic REMS has the nucleotide sequence GAgurngn at the RNA level, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n is any nucleotide. In another specific aspect, the intronic REMS has the nucleotide sequence GAguragu at the RNA level, wherein r is adenine or guanine. In one or more of such specific aspects provided herein, n is adenine or guanine. In a more specific aspect, the intronic REMS has the nucleotide sequence NNGAgurngn (SEQ ID NO: 1) at the RNA level, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n or N is any nucleotide. In another more specific aspect, the intronic REMS has the nucleotide sequence NNGAguragu (SEQ ID NO: 2) at the RNA level, wherein r is adenine or guanine and N is any nucleotide. In one or more of such more specific aspects provided herein, N is adenine or guanine. In another specific aspect, the intronic REMS is downstream of an intronic branch point and a functional intronic 3′ splice site, wherein the intronic REMS comprises a nucleotide sequence selected from the group consisting of ANGAgurngn (SEQ ID NO: 4), CNGAgurngn (SEQ ID NO: 5), GNGAgurngn (SEQ ID NO: 6), UNGAgurngn (SEQ ID NO: 7), NAGAgurngn (SEQ ID NO: 8), NCGAgurngn (SEQ ID NO: 9), NGGAgurngn (SEQ ID NO: 10), NUGAgurngn (SEQ ID NO: 11), AAGAgurngn (SEQ ID NO: 12), ACGAgurngn (SEQ ID NO: 13), AGGAgurngn (SEQ ID NO: 14), AUGAgurngn (SEQ ID NO: 15), CAGAgurngn (SEQ ID NO: 16), CCGAgurngn (SEQ ID NO: 17), CGGAgurngn (SEQ ID NO: 18), CUGAgurngn (SEQ ID NO: 19), GAGAgurngn (SEQ ID NO: 20), GCGAgurngn (SEQ ID NO: 21), GGGAgurngn (SEQ ID NO: 22), GUGAgurngn (SEQ ID NO: 23), UAGAgurngn (SEQ ID NO: 24), UCGAgurngn (SEQ ID NO: 25), UGGAgurngn (SEQ ID NO: 52) and UUGAgurngn (SEQ ID NO: 53) at the RNA level, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n or N is any nucleotide, by which the intronic REMS, in the presence of a compound described herein, functions as an intronic 5′ splice site, causing the NNGA nucleotides of the REMS and the intronic nucleotides between the intronic 3′ splice site down to and including the NNGA nucleotides to be spliced into the mature RNA as an intronic exon to provide a non-wild-type, nonfunctional mRNA. In another specific aspect, the intronic REMS is upstream of an intronic branch point and a functional intronic 3′ splice site, wherein the intronic REMS comprises a nucleotide sequence selected from the group consisting of ANGAgurngn (SEQ ID NO: 4), CNGAgurngn (SEQ ID NO: 5), GNGAgurngn (SEQ ID NO: 6), UNGAgurngn (SEQ ID NO: 7), NAGAgurngn (SEQ ID NO: 8), NCGAgurngn (SEQ ID NO: 9), NGGAgurngn (SEQ ID NO: 10), NUGAgurngn (SEQ ID NO: 11), AAGAgurngn (SEQ ID NO: 12), ACGAgurngn (SEQ ID NO: 13), AGGAgurngn (SEQ ID NO: 14), AUGAgurngn (SEQ ID NO: 15), CAGAgurngn (SEQ ID NO: 16), CCGAgurngn (SEQ ID NO: 17), CGGAgurngn (SEQ ID NO: 18), CUGAgurngn (SEQ ID NO: 19), GAGAgurngn (SEQ ID NO: 20), GCGAgurngn (SEQ ID NO: 21), GGGAgurngn (SEQ ID NO: 22), GUGAgurngn (SEQ ID NO: 23), UAGAgurngn (SEQ ID NO: 24), UCGAgurngn (SEQ ID NO: 25), UGGAgurngn (SEQ ID NO: 52) and UUGAgurngn (SEQ ID NO: 53) at the RNA level, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n or N is any nucleotide, by which the intronic REMS, in the presence of a compound described herein, functions as an intronic 5′ splice site, causing the NNGA nucleotides of the REMS and the intronic nucleotides between the intronic 3′ splice site down to and including the NNGA nucleotides to be spliced into the mature RNA as an intronic exon to provide a non-wild-type, nonfunctional mRNA. In a preferred aspect, the REMS has a nucleotide sequence selected from the group consisting of ANGAguragu (SEQ ID NO: 28), CNGAguragu (SEQ ID NO: 29), GNGAguragu (SEQ ID NO: 30), UNGAguragu (SEQ ID NO: 31), NAGAguragu (SEQ ID NO: 32), NCGAguragu (SEQ ID NO: 33), NGGAguragu (SEQ ID NO: 34), NUGAguragu (SEQ ID NO: 35), AAGAguragu (SEQ ID NO: 36), ACGAguragu (SEQ ID NO: 37), AGGAguragu (SEQ ID NO: 38), AUGAguragu (SEQ ID NO: 39), CAGAguragu (SEQ ID NO: 40), CCGAguragu (SEQ ID NO: 41), CGGAguragu (SEQ ID NO: 42), CUGAguragu (SEQ ID NO: 43), GAGAguragu (SEQ ID NO: 44), GCGAguragu (SEQ ID NO: 45), GGGAguragu (SEQ ID NO: 46), GUGAguragu (SEQ ID NO: 47), UAGAguragu (SEQ ID NO: 48), UCGAguragu (SEQ ID NO: 49), UGGAguragu (SEQ ID NO: 489) and UUGAguragu (SEQ ID NO: 508) at the RNA level, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and N is any nucleotide. In one or more aspects provided herein, N is adenine or guanine.
(5) In the context of DNA, in a specific aspect, the nucleotide sequence encoding an intronic REMS has the sequence Gagtrngn, wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n is any nucleotide. In another specific aspect, in the context of DNA, the nucleotide sequence encoding an intronic REMS has the sequence Gagtragt, wherein r is adenine or guanine. In a specific aspect, in the context of DNA, the nucleotide sequence encoding an intronic REMS has the sequence NNGAgtrngn (SEQ ID NO: 1808), wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n or N is any nucleotide. In another specific aspect, in the context of DNA, the nucleotide sequence encoding an intronic REMS has the sequence NNGAgtragt (SEQ ID NO: 3634), wherein r is adenine or guanine and N is any nucleotide. In a specific aspect, in the context of DNA, the nucleotide sequence encoding an intronic REMS comprises a sequence selected from the group consisting of ANGAgtrngn (SEQ ID NO: 1809), CNGAgtrngn (SEQ ID NO: 1810), GNGAgtrngn (SEQ ID NO: 1811), TNGAgtrngn (SEQ ID NO: 1812), NAGAgtrngn (SEQ ID NO: 1813), NCGAgtrngn (SEQ ID NO: 1814), NGGAgtrngn (SEQ ID NO: 1815), NTGAgtrngn (SEQ ID NO: 1816), AAGAgtrngn (SEQ ID NO: 1817), ACGAgtrngn (SEQ ID NO: 1818), AGGAgtrngn (SEQ ID NO: 1819), ATGAgtrngn (SEQ ID NO: 1820), CAGAgtrngn (SEQ ID NO: 1821), CCGAgtrngn (SEQ ID NO: 1822), CGGAgtrngn (SEQ ID NO: 1823), CTGAgtrngn (SEQ ID NO: 1824), GAGAgtrngn (SEQ ID NO: 1825), GCGAgtrngn (SEQ ID NO: 1826), GGGAgtrngn (SEQ ID NO: 1827), GTGAgtrngn (SEQ ID NO: 1828), TAGAgtrngn (SEQ ID NO: 1829), TCGAgtrngn (SEQ ID NO: 1830), TGGAgtrngn (SEQ ID NO: 1831) and TTGAgtrngn (SEQ ID NO: 1832), wherein r is A or G (i.e., a purine nucleotide adenine or guanine) and n or N is any nucleotide. In a preferred aspect, in the context of DNA, the nucleotide sequence encoding the intronic REMS comprises a sequence selected from the group consisting of ANGAgtragt (SEQ ID NO: 1833), CNGAgtragt (SEQ ID NO: 1834), GNGAgtragt (SEQ ID NO: 1835), TNGAgtragt (SEQ ID NO: 1836), NAGAgtragt (SEQ ID NO: 1837), NCGAgtragt (SEQ ID NO: 1838), NGGAgtragt (SEQ ID NO: 1839), NTGAgtragt (SEQ ID NO: 1840), AAGAgtragt (SEQ ID NO: 1841), ACGAgtragt (SEQ ID NO: 1842), AGGAgtragt (SEQ ID NO: 1843), ATGAgtragt (SEQ ID NO: 1844), CAGAgtragt (SEQ ID NO: 1845), CCGAgtragt (SEQ ID NO: 1846), CGGAgtragt (SEQ ID NO: 1847), CTGAgtragt (SEQ ID NO: 1848), GAGAgtragt (SEQ ID NO: 1849), GCGAgtragt (SEQ ID NO: 1850), GGGAgtragt (SEQ ID NO: 1851), GTGAgtragt (SEQ ID NO: 1852), TAGAgtragt (SEQ ID NO: 1853), TCGAgtragt (SEQ ID NO: 1854), TGGAgtragt (SEQ ID NO: 1855) and TTGAgtragt (SEQ ID NO: 1856), wherein r is adenine or guanine and N is any nucleotide. In one or more aspects provided herein, N is adenine or guanine.
(6) An intronic REMS can be part of an endogenous RNA or can be introduced into an RNA sequence that does not naturally contain the intronic REMS sequence (in which case, the introduced intronic REMS is a non-endogenous intronic REMS, i.e., an intronic REMS not naturally present in the corresponding RNA. A nucleotide sequence encoding an intronic REMS can also be part of an endogenous DNA sequence, or a nucleotide sequence encoding the intronic REMS can be introduced into a DNA sequence that does not naturally contain the nucleotide sequence encoding an intronic REMS.
(7) In a specific aspect, the REMS is located in an intron and is upstream of a branch point and a functional 3′ splice site which, in the presence of a small molecule splicing modifier, enables the REMS to function as a 5′ splice site. Without being bound by any theory or mechanism, the small molecule compounds described herein have been shown to increase the affinity of the interaction between the U1 snRNP, as well as other components of the pre-mRNA splicing machinery, and the nucleotides NNGA of the REMS whereby, in the presence of the compound, the intronic REMS functions as a U1 snRNP binding site, causing the intronic nucleotides to be spliced as an intronic exon.
(8) Compound Use
(9) In one aspect provided herein are compounds of Formula (I) for use in the methods described herein:
(10) ##STR00040## or a form thereof, wherein W is CH═CH or S; X is CH.sub.2, CH(C.sub.1-4alkyl), C(C.sub.1-4alkyl).sub.2, CH═CH, O, NR.sub.5, or a bond; A is aryl, heteroaryl, heterocyclyl, or C.sub.9-10cycloalkyl, wherein aryl is selected from phenyl and naphthyl, each optionally substituted with 1, 2, 3, or 4 substituents each selected from R.sub.1, wherein heteroaryl is a saturated monocyclic, bicyclic or tricyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R.sub.1, wherein heterocyclyl is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R.sub.2, and wherein C.sub.9-10cycloalkyl is a saturated or partially unsaturated bicyclic ring system optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R.sub.2; B is heterocyclyl, wherein heterocyclyl is a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R.sub.4; R.sub.1 is halogen, hydroxyl, cyano, C.sub.1-4alkyl, halo-C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino, amino-C.sub.1-4alkyl, C.sub.1-4alkyl-amino-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkyl, amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl, (C.sub.1-4alkyl).sub.2-amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-carbonyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl-amino, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, hydroxyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl, C.sub.1-4alkoxy, halo-C.sub.1-4alkoxy, amino-C.sub.1-4alkoxy, hydroxyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-amino-C.sub.1-4alkoxy, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkoxy, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkoxy, C.sub.1-4alkoxy-C.sub.1-4alkoxy, C.sub.1-4alkoxy-carbonyl, C.sub.1-4alkoxy-carbonyl-amino, C.sub.1-4alkoxy-carbonyl-amino-C.sub.1-4alkoxy, C.sub.2-4alkenyl, C.sub.2-4alkenyl-amino-carbonyl, C.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl-C.sub.1-4alkoxy, C.sub.3-7cycloalkenyl, heteroaryl, heteroaryl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, heterocyclyl, heterocyclyl-C.sub.1-4alkyl, heterocyclyl-C.sub.1-4alkoxy, phenyl, or phenyl-C.sub.1-4alkoxy, wherein heteroaryl is a saturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, wherein heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R.sub.3; R.sub.2 is halogen, hydroxyl, cyano, oxo, hydroxyl-imino, C.sub.1-4alkyl, halo-C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino, amino-C.sub.1-4alkyl, C.sub.1-4alkyl-amino-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkyl, amino-carbonyl, hydroxyl-C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkoxy-carbonyl, C.sub.2-4alkenyl, C.sub.3-7cycloalkyl, or heterocyclyl-C.sub.1-4alkyl, wherein heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and wherein each instance of heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R.sub.3; R.sub.3 is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, C.sub.1-4alkyl, halo-C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino, amino-C.sub.1-4alkyl, C.sub.1-4alkyl-amino-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkyl, amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl, (C.sub.1-4alkyl).sub.2-amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-carbonyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl-amino, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, hydroxyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl, C.sub.1-4alkoxy, halo-C.sub.1-4alkoxy, amino-C.sub.1-4alkoxy, hydroxyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-amino-C.sub.1-4alkoxy, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkoxy, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkoxy, C.sub.1-4alkoxy-C.sub.1-4alkoxy, C.sub.1-4alkoxy-carbonyl, C.sub.1-4alkoxy-carbonyl-amino, C.sub.1-4alkoxy-carbonyl-amino-C.sub.1-4alkoxy, C.sub.2-4alkenyl, C.sub.2-4alkenyl-amino-carbonyl, C.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl-C.sub.1-4alkoxy, C.sub.3-7cycloalkenyl, heteroaryl, heteroaryl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, heterocyclyl, heterocyclyl-C.sub.1-4alkyl, phenyl, or phenyl-C.sub.1-4alkoxy; R.sub.4 is independently selected from halogen, C.sub.1-4alkyl, hydroxyl-C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino or hydroxyl-C.sub.1-4alkyl-amino; and R.sub.5 is hydrogen, C.sub.1-4alkyl, or hydroxyl-C.sub.1-4alkyl; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(11) In another aspect provided herein are compounds of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib) for use in the methods described herein:
(12) ##STR00041## or a form thereof, wherein X is CH.sub.2, CH(C.sub.1-4alkyl), C(C.sub.1-4alkyl).sub.2, CH═CH, O, NR.sub.5, or a bond; A is aryl, heteroaryl, heterocyclyl, or C.sub.9-10cycloalkyl, wherein aryl is selected from phenyl and naphthyl, each optionally substituted with 1, 2, 3, or 4 substituents each selected from R.sub.1, wherein heteroaryl is a saturated monocyclic, bicyclic or tricyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R.sub.1, wherein heterocyclyl is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R.sub.2, and wherein C.sub.9-10cycloalkyl is a saturated or partially unsaturated bicyclic ring system optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R.sub.2; B is heterocyclyl, wherein heterocyclyl is a saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R.sub.4, R.sub.1 is halogen, hydroxyl, cyano, C.sub.1-4alkyl, halo-C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino, amino-C.sub.1-4alkyl, C.sub.1-4alkyl-amino-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkyl, amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl-amino, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, hydroxyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl, C.sub.1-4alkoxy, halo-C.sub.1-4alkoxy, amino-C.sub.1-4alkoxy, hydroxyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-amino-C.sub.1-4alkoxy, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkoxy, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkoxy, C.sub.1-4alkoxy-C.sub.1-4alkoxy, C.sub.1-4alkoxy-carbonyl, C.sub.1-4alkoxy-carbonyl-amino, C.sub.1-4alkoxy-carbonyl-amino-C.sub.1-4alkoxy, C.sub.2-4alkenyl, C.sub.2-4alkenyl-amino-carbonyl, C.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl-C.sub.1-4alkoxy, C.sub.3-7cycloalkenyl, heteroaryl, heteroaryl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, heterocyclyl, heterocyclyl-C.sub.1-4alkyl, heterocyclyl-C.sub.1-4alkoxy, phenyl, or phenyl-C.sub.1-4alkoxy, wherein heteroaryl is a saturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, wherein heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R.sub.3; R.sub.2 is halogen, hydroxyl, cyano, oxo, hydroxyl-imino, C.sub.1-4alkyl, halo-C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino, amino-C.sub.1-4alkyl, amino-carbonyl, hydroxyl-C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkoxy-carbonyl, C.sub.2-4alkenyl, C.sub.3-7cycloalkyl, or heterocyclyl-C.sub.1-4alkyl; R.sub.3 is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino, amino-C.sub.1-4alkyl, C.sub.1-4alkyl-amino-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkyl, amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl-amino, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, hydroxyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl, C.sub.1-4alkoxy, halo-C.sub.1-4alkoxy, amino-C.sub.1-4alkoxy, hydroxyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-amino-C.sub.1-4alkoxy, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkoxy, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkoxy, C.sub.1-4alkoxy-C.sub.1-4alkoxy, C.sub.1-4alkoxy-carbonyl, C.sub.1-4alkoxy-carbonyl-amino, C.sub.1-4alkoxy-carbonyl-amino-C.sub.1-4alkoxy, C.sub.2-4alkenyl, C.sub.2-4alkenyl-amino-carbonyl, C.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl-C.sub.1-4alkoxy, C.sub.3-7cycloalkenyl, heteroaryl, heteroaryl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, heterocyclyl, heterocyclyl-C.sub.1-4alkyl, phenyl, or phenyl-C.sub.1-4alkoxy; R.sub.4 is independently selected from halogen, C.sub.1-4alkyl, hydroxyl-C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino or hydroxyl-C.sub.1-4alkyl-amino; and R.sub.5 is hydrogen, C.sub.1-4alkyl, or hydroxyl-C.sub.1-4alkyl; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(13) In another aspect provided herein are compounds of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib) for use in the methods described herein:
(14) ##STR00042## or a form thereof, wherein X is O, NH, N(CH.sub.3) or a bond; A is aryl, heteroaryl or heterocyclyl, wherein aryl is selected from the group consisting of
(15) ##STR00043## wherein heteroaryl is selected from the group consisting of
(16) ##STR00044## ##STR00045## ##STR00046## ##STR00047## wherein heterocyclyl is selected from the group consisting of
(17) ##STR00048## ##STR00049## B is heterocyclyl selected from the group consisting of
(18) ##STR00050## ##STR00051## ##STR00052## R.sub.1a, R.sub.1b and R.sub.1c are each, where allowed by available valences, one or more substituents each selected from halogen, hydroxyl, cyano, C.sub.1-4alkyl, halo-C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino, amino-C.sub.1-4alkyl, C.sub.1-4alkyl-amino-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkyl, amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl, (C.sub.1-4alkyl).sub.2-amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-carbonyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl-amino, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, hydroxyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl, C.sub.1-4alkoxy, halo-C.sub.1-4alkoxy, amino-C.sub.1-4alkoxy, hydroxyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-amino-C.sub.1-4alkoxy, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkoxy, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkoxy, C.sub.1-4alkoxy-C.sub.1-4alkoxy, C.sub.1-4alkoxy-carbonyl, C.sub.1-4alkoxy-carbonyl-amino, C.sub.1-4alkoxy-carbonyl-amino-C.sub.1-4alkoxy, C.sub.2-4alkenyl, C.sub.2-4alkenyl-amino-carbonyl, C.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl-C.sub.1-4alkoxy, C.sub.3-7cycloalkenyl, heteroaryl, heteroaryl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, heterocyclyl, heterocyclyl-C.sub.1-4alkyl, heterocyclyl-C.sub.1-4alkoxy, phenyl, or phenyl-C.sub.1-4alkoxy, wherein heteroaryl is a saturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, wherein heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R.sub.3; R.sub.2a, R.sub.2b and R.sub.2c are each, where allowed by available valences, one or more substituents each selected from halogen, hydroxyl, cyano, oxo, hydroxyl-imino, C.sub.1-4alkyl, halo-C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino, amino-C.sub.1-4alkyl, C.sub.1-4alkyl-amino-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkyl, amino-carbonyl, hydroxyl-C.sub.1-4alkyl, C.sub.1-4alkoxy, C.sub.1-4alkoxy-carbonyl, C.sub.2-4alkenyl, C.sub.3-7cycloalkyl, or heterocyclyl-C.sub.1-4alkyl, wherein heterocyclyl is a saturated or partially unsaturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and wherein each instance of heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R.sub.3; R.sub.3 is halogen, hydroxyl, nitro, oxo, hydroxyl-imino, C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino, amino-C.sub.1-4alkyl, C.sub.1-4alkyl-amino-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkyl, amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl, (C.sub.1-4alkyl).sub.2-amino-carbonyl, C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, (C.sub.1-4alkyl).sub.2-amino-carbonyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl-amino, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, hydroxyl-C.sub.1-4alkyl, C.sub.1-4alkyl-carbonyl, C.sub.1-4alkoxy, halo-C.sub.1-4alkoxy, amino-C.sub.1-4alkoxy, hydroxyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-C.sub.1-4alkoxy, C.sub.1-4alkyl-amino-C.sub.1-4alkoxy, (C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkoxy, C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkoxy, C.sub.1-4alkoxy-C.sub.1-4alkoxy, C.sub.1-4alkoxy-carbonyl, C.sub.1-4alkoxy-carbonyl-amino, C.sub.1-4alkoxy-carbonyl-amino-C.sub.1-4alkoxy, C.sub.2-4alkenyl, C.sub.2-4alkenyl-amino-carbonyl, C.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl-C.sub.1-4alkoxy, C.sub.3-7cycloalkenyl, heteroaryl, heteroaryl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino, heteroaryl-C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl, heteroaryl-C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl, heterocyclyl, heterocyclyl-C.sub.1-4alkyl, phenyl, or phenyl-C.sub.1-4alkoxy; and R.sub.4a, R.sub.4b, R.sub.4c, R.sub.4d, R.sub.4e, R.sub.4f and R.sub.4g are independently selected from halogen, C.sub.1-4alkyl, hydroxyl-C.sub.1-4alkyl, amino, C.sub.1-4alkyl-amino, (C.sub.1-4alkyl).sub.2-amino or hydroxyl-C.sub.1-4alkyl-amino; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(19) In another aspect provided herein are compounds of Formula (I) for use in the methods described herein, wherein the compound of Formula (I) is selected from a compound of Formula (Ia11), Formula (Ia15), Formula (Ia18) or Formula (Ib1):
(20) ##STR00053## or a form thereof, wherein (when present), X is selected from O, NR.sub.5, or a bond; A is selected from phenyl, thiophenyl, indazolyl, pyridinyl, pyrimidinyl or phenoxy, wherein phenyl and phenoxy are each optionally substituted with 1, 2 or 3 substituents each selected from R.sub.1a, wherein thiophenyl, indazolyl, pyridinyl, pyrimidinyl are each optionally substituted with 1 or 2 substituents each selected from R.sub.1a, B is selected from 1H-pyrazolyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, 2,6-diazaspiro[3.4]octyl or 2,7-diazaspiro[3.5]nonyl, each optionally substituted with 1 or 2 substituents each selected from R.sub.4a; R.sub.1a is selected from halogen, hydroxyl, C.sub.1-4alkyl, halo-C.sub.1-4alkyl, amino, C.sub.1-4alkoxy, or heteroaryl, wherein heteroaryl is a saturated monocyclic or bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S optionally substituted with 1 or 2 substituents each selected from R.sub.3a; R.sub.3a is selected from nitro or C.sub.1-4alkyl; and, R.sub.4a is C.sub.1-4alkyl; R.sub.5a is hydrogen, C.sub.1-4alkyl, or hydroxyl-C.sub.1-4alkyl; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(21) Another aspect of the present description relates to a compound of Formula (I) selected from a compound of Formula (Ia11), Formula (Ia15), Formula (Ia18) or Formula (Ib1): or a form thereof, wherein (when present), R.sub.1a is selected from fluoro, chloro, hydroxyl, methyl, difluoromethyl, amino, methoxy or 1H-pyrazolyl or 1H-imidazol-1-yl, wherein 1H-pyrazolyl is optionally substituted with 1 or 2 substituents each selected from R.sub.3a; R.sub.3a is selected from nitro or methyl or amino; and, R.sub.4a is methyl or ethyl; R.sub.5a is hydrogen or methyl; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(22) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia1) or a form thereof, wherein substituents R.sub.1a, R.sub.1b, and X, when present, are indicated in the table below with multiple substituents separated by a comma; and, “- -” indicates that one or more R.sub.1a, R.sub.1b, and X substituents are not present:
(23) TABLE-US-00003
(24) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia2) or a form thereof, wherein substituents R.sub.1a, R.sub.1b, and R.sub.4a, when present, are indicated in the table below with multiple substituents separated by a comma; and, “- -” indicates that one or more R.sub.1a, R.sub.1b, and R.sub.4a substituents are not present:
(25) TABLE-US-00004 (Ia2)
(26) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia3) or a form thereof, wherein substituents R.sub.1a, R.sub.1b and X, when present, are indicated in the table below with multiple substituents separated by a comma; and, “- -” indicates that one or more R.sub.1a, R.sub.1b and X substituents are not present:
(27) TABLE-US-00005 (Ia3)
(28) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia4) or a form thereof, wherein substituents X, R.sub.1a, R.sub.1b and R.sub.4a, when present, are indicated in the table below; and, “- -” indicates that one or more X, R.sub.1a, R.sub.1b and R.sub.4a substituents are not present:
(29) TABLE-US-00006 (Ia4)
(30) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia5) or a form thereof, wherein substituents R.sub.1a and R.sub.1b, when present, are indicated in the table below with multiple substituents separated by a comma; and, “- -” indicates that one or more R.sub.1a and R.sub.1b substituents are not present:
(31) TABLE-US-00007 (Ia5)
(32) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia6) or a form thereof, wherein substituents R.sub.1a, when present, are indicated in the table below; and, “- -” indicates that one or more R.sub.1a substituents are not present:
(33) TABLE-US-00008 (Ia6)
(34) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia7) or a form thereof, wherein substituents R.sub.1a, when present, are indicated in the table below; and, “- -” indicates that one or more R.sub.1a substituents are not present:
(35) TABLE-US-00009 (Ia7)
(36) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia8) or a form thereof, wherein substituents R.sub.1a and B, when present, are indicated in the table below; and, “- -” indicates that one or more R.sub.1a and B substituents are not present:
(37) TABLE-US-00010 (Ia8)
(38) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia9) or a form thereof, wherein substituents R.sub.1a and B, when present, are indicated in the table below; and “- -” indicates that one or more R.sub.1a and B substituents are not resent:
(39) TABLE-US-00011 (Ia9)
(40) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia10) or a form thereof, wherein substituents R.sub.1a and B, when present, are indicated in the table below; and, “- -” indicates that one or more R.sub.1a and B substituents are not present:
(41) TABLE-US-00012 (Ia10)
(42) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia11) or a form thereof, wherein substituents A, X and R.sub.4a, when present, are indicated in the table below; and, “- -” indicates that one or more A, X and R.sub.4a substituents are not present:
(43) TABLE-US-00013 (Ia11)
(44) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia11) or a form thereof, wherein substituents A, X and R.sub.4a, when present, are indicated in the table below; and, “- -” indicates that one or more A, X and R.sub.4a substituents are not present:
(45) TABLE-US-00014 (Ia11)
(46) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia11) or a form thereof, wherein substituents A, X and R.sub.4a, when present, are indicated in the table below; and, “- -” indicates that one or more A, X and R.sub.4a substituents are not present:
(47) TABLE-US-00015 (Ia11)
(48) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia12) or a form thereof, wherein substituents X, R.sub.1a and B, when present, are indicated in the table below; and, “- -” indicates that one or more X, R.sub.1a and B substituents are not present:
(49) TABLE-US-00016 (Ia12)
(50) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia13) or a form thereof, wherein substituents X, R.sub.1a and R.sub.4a, when present, are indicated in the table below; and, “- -” indicates that one or more X, R.sub.1a and R.sub.4a substituents are not present:
(51) TABLE-US-00017 (Ia13)
(52) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia14) or a form thereof, wherein substituents X and B, when present, are indicated in the table below; and, “- -” indicates that one or more X and B substituents are not present:
(53) TABLE-US-00018 (Ia14)
(54) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia15) or a form thereof, wherein substituents X, R.sub.1a and R.sub.4a, when present, are indicated in the table below; and, “- -” indicates that one or more X, R.sub.1a and R.sub.4a substituents are not present:
(55) TABLE-US-00019 (Ia15)
(56) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia15) or a form thereof, wherein substituents X, R.sub.1a and R.sub.4a, when present, are indicated in the table below; and, “- -” indicates that one or more X, R.sub.1a and R.sub.4a substituents are not present:
(57) TABLE-US-00020 (Ia15)
(58) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia16) or a form thereof, wherein substituents R.sub.1a and R.sub.4a, when present, are indicated in the table below; and, “- -” indicates that one or more R.sub.1a and R.sub.4a substituents are not present:
(59) TABLE-US-00021 (Ia16)
(60) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia17) or a form thereof, wherein substituent R.sub.1a, when present, is indicated in the table below; and, “- -” indicates that one or more R.sub.1a substituents are not present:
(61) TABLE-US-00022 (Ia17)
(62) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia18) or a form thereof, wherein substituent X and B, when present, is indicated in the table below; and, “- -” indicates that one or more X and B substituents are not present:
(63) TABLE-US-00023 (Ia18)
(64) In another aspect provided herein are compounds of Formula (Ia) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ia18) or a form thereof, wherein substituents X, R.sub.1a and B, when present, are indicated in the table below; and, “- -” indicates that one or more X, R.sub.1a and B substituents are not present:
(65) TABLE-US-00024 (Ia18)
(66) In another aspect provided herein are compounds of Formula (Ib) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ib1) or a form thereof, wherein substituent A is indicated in the table below:
(67) TABLE-US-00025 (Ib1)
(68) In another aspect provided herein are compounds of Formula (Ib) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ib1) or a form thereof, wherein substituent A is indicated in the table below: c
(69) TABLE-US-00026 Cpd A 462 3-(1H-pyrazol-4-yl)phenoxy 463 4-(1H-pyrazol-4-yl)phenoxy
(70) In another aspect provided herein are compounds of Formula (Ib) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ib1) or a form thereof, wherein substituent A is indicated in the table below:
(71) TABLE-US-00027 (Ib1)
(72) In another aspect provided herein are compounds of Formula (Ib) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ib2) or a form thereof, wherein substituent A is indicated in the table below:
(73) TABLE-US-00028 (Ib2)
(74) In another aspect provided herein are compounds of Formula (Ib) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ib3) or a form thereof, wherein substituents R.sub.1a, R.sub.1b and B, when present, are indicated in the table below; and, “- -” indicates that one or more R.sub.1a, R.sub.1b and B substituents are not present:
(75) TABLE-US-00029 (Ib3)
(76) In another aspect provided herein are compounds of Formula (Ib) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ib) or a form thereof, wherein substituents R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d (each representative of the scope of R.sub.1) and X, when present, are indicated in the table below; and, “- -” indicates that one or more R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d and X substituents are not present:
(77) TABLE-US-00030 (Ib4)
(78) In another aspect provided herein are compounds of Formula (Ib) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ib5) or a form thereof, wherein substituents R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d (each representative of the scope of R.sub.1) and R.sub.4a, when present, are indicated in the table below; and, “- -” indicates that one or more R.sub.1a, R.sub.1b, R.sub.1c, R.sub.1d and R.sub.4a substituents are not present:
(79) TABLE-US-00031 (Ib5)
(80) In another aspect provided herein are compounds of Formula (Ib) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ib6) or a form thereof, wherein (substituents R.sub.1a, R.sub.1b, R.sub.1c and R.sub.1d (each representative of the scope of R.sub.1), when present, are indicated in the table below; and, “- -” indicates that one or more R.sub.1a, R.sub.1b, R.sub.1c and R.sub.1d substituents are not present:
(81) TABLE-US-00032 (Ib6)
(82) In another aspect provided herein are compounds of Formula (Ib) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ib7) or a form thereof, wherein substituent R.sub.1b, when present, is indicated in the table below:
(83) TABLE-US-00033 (Ib7)
(84) In another aspect provided herein are compounds of Formula (Ib) or a form thereof for use in the methods described herein, wherein the compound is selected from a compound of Formula (Ib8) or a form thereof, wherein substituent R.sub.1b, when present, is indicated in the table
(85) TABLE-US-00034 (Ib8)
Preparation of Compounds
(86) Compounds provided herein can be prepared by those skilled in the art, such as, by the synthetic methods set forth in International Application Number PCT/US2013/054687 filed Aug. 13, 2013 and published as International Publication Number WO2014/028459 on Feb. 20, 2014; International Application Number PCT/US2014/012774 filed Jan. 23, 2014 and published as International Publication Number WO2014/116845 A1 on Jul. 31, 2014; International Application Number PCT/US2014/048984 filed Jul. 30, 2014 and published as International Publication Number WO2015/017589 on Feb. 5, 2015; and, International Application Number PCT/US2016/066042 filed Dec. 11, 2016 and published as International Publication Number WO2017/100726 on Jun. 15, 2017, each of which are incorporated by reference in their entirety as if fully set forth herein.
(87) In one aspect, the compound of Formula (I) used in a method disclosed herein is a compound selected from the group consisting of:
(88) ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##
(89) ##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172##
(90) wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(91) In another aspect, the compound of Formula (I) used in a method disclosed herein is a compound selected from the group consisting of:
(92) ##STR00173## ##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181## ##STR00182##
(93) wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(94) In another aspect, the compound of Formula (I) or a form thereof used in a method disclosed herein is a compound of Formula (I) or a form thereof (wherein compound number (#.sup.1) indicates that the salt form was isolated) selected from the group consisting of:
(95) TABLE-US-00035 Cpd Name 1 6-(naphthalen-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 2 6-(benzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3- amine 3 2-(6-(2,2,6,6-tetramethylpiperidin-4-yl-amino)-pyridazin-3-yl)phenol 4 2-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzo[b]- thiophene-5-carbonitrile 5 6-(quinolin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 6 3-(benzo[b]-thiophen-2-yl)-6-(2,2,6,6-tetramethylpiperidin-4-yl-oxy)pyridazine 7 2-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)-pyridazin-3-yl)phenol 8 6-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)amino)-pyridazin-3-yl)naphthalen-2-ol 9 6-(benzo[b]-thiophen-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 10 7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline 11 6-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline 12 N-methyl-6-(quinolin-7-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 13 N-methyl-6-(quinolin-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-aniine 14 6-(isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 15 6-(isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 16 6-(imidazo[1,2-a]pyridin-6-yl-pyridazin-3-yl)-methyl-(2,2,6,6-tetramethylpiperidin-4- yl)-amine 17 N-methyl-6-(6-phenylpyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3- amine 18 6-(6-(1H-pyrrol-1-yl)pyridin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 19 6-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 20 methyl-(6-quinoxalin-2-yl-pyridazin-3-yl)-(2,2,6,6-tetramethylpiperidin-4-yl)-amine 21 methyl-(6-quinolin-3-yl-pyridazin-3-yl)-(2,2,6,6-tetramethylpiperidin-4-yl)-amine 22 N-methyl-6-(phthalazin-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 23 6-(benzo[c][1,2,5]oxa-diazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3- amine 24 6-(benzo[d]thiazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine 25 6-(2-methylbenzo-[d]oxazol-6-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3- amine 26 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol 27 5-chloro-2-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol 28 3-(6-(2,2,6,6-tetramethylpiperidin-4-yl-amino)pyridazin-3-yl)naphthalen-2-ol 29 5-chloro-2-(6-(1,2,2,6,6-pentamethylpiperidin-4-ylamino)pyridazin-3-yl)phenol 30 4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)benzonitrile 31 3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalen-2-ol 32.sup.1 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- (trifluoromethyl)phenol 33 2-fluoro-6-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)-amino)-pyridazin-3-yl)phenol 34 3,5-dimethoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol 35 4,5-dimethoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol 36 5-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol 37 4,5-difluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol 38 5-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol 39 3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)benzonitrile 40 1-allyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalen-2-ol 41 6-(benzo[b]thiophen-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine 42 N-allyl-3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)benzamide 43 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-1- yl)phenol 44 5-(5-methyl-oxazol-2-yl)-2-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)-amino)- pyridazin-3-yl)phenol 45 5-(4-hydroxymethyl)-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 46 5-(1H-imidazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenol 47 5-(4-amino-1H-pyrazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 48 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4- yl)phenol 49 5-(3-amino-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 50 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-(2- morpholino-ethyl)-1H-pyrazol-4-yl)phenol 51 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H- pyrazol-4-yl)phenol 52 5-(5-amino-1H-pyrazol-1-yr)-2-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 53.sup.1 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-1- yl)phenol 54 2-((6-((2-hydroxy-ethyl)-(2,2,6,6-tetramethylpiperidin-4-yl)-amino)-pyridazin-3-yl)-5- pyrazol-1-yl)phenol 55 2-(6-(piperidin-4-yloxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 56 2-(6-(((2S,4R,6R)-2,6-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1- yl)phenol 57 2-(6-((-2,6-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 58 5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-yl-oxy)pyridazin-3-yl)phenol 59 2-(6-(((2S,4S)-2-methylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 60 (5-(1H-pyrazol-1-yl)-2-(6-(pyrrolidin-3-ylmethoxy)pyridazin-3-yl)phenol 61 2-(6-((3-fluoropiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 62 2-(6-(1,2,2,6,6-pentamethyl-piperidin-4-yl-oxy)-pyridazin-3-yl)-5-(1H-pyrazol-1- y1)phenol 63 5-1H-pyrazol-1-yl-2-(6-(2,2,6,6-tetramethylpiperidin-4-yl-oxy)-pyridazin-3-yl)phenol 64 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol 65.sup.1 2-(6-piperazin-1-yl-pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 66 3-(6-(azetidin-3-ylamino)-pyridazin-3-yl)naphthalen-2-ol 67 2-(6-(azetidin-3-ylamino)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 68 2-(6-(3,5-dimethylpiperazin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 69 2-(6-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridazin-3-yl)-5-(1H-pyrazol-1- yl)phenol 70 2-(6-(1,4-diazepan-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 71 2-(6-(4-(2-hydroxyethyl)piperazin-1-yi)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 72 2-(6-(3,6-diazabicyclo[3.2.1]octan-3-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 73 2-(6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 74 2-(6-(3-(hydroxymethyl)piperazin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 75 2-(6-(1,7-diazaspiro[4.4]nonan-7-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 76 2-(6-(4-amino-4-methylpiperidin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 77 2-(6-(3-(dimethylamino)piperidin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 78 2-(6-(1, 2,2,6,6-pentamethylpiperidin-4-ylamino)-pyridazin-3-yl)-5-1H-pyrazol-1-yl- phenol 79 2-(6-(3,3-dimethylpiperazin-1-yl)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 80 2-(6-(7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]-nonan-2-yl)pyridazin-3-yl)-5-(1H-pyrazol- 1-yl)phenol 81 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H- pyrazol-1-yl)phenol 82.sup.1 3-(6-(piperazin-1-yl)pyridazin-3-yl)naphthalene-2,7-diol 83 5-(1H-pyrazol-1-yl)-2-(6-(1,2,3,6-tetrahydropyridin-4-yr)pyridazin-3-yl)phenol 84 2-(6-piperidin-4-yl-pyridazin-3-yl)-5-1H-pyrazol-1-yl-phenol 85 3-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalen-2-ol 86.sup.1 3-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol 87 3-(6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7- diol 88.sup.1 3-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol 89.sup.1 3-(6-(piperidin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol 90 3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)naphthalene-2,7-diol 91 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7- diol 92 3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalene-2,7-diol 93 tert-butyl (3-((7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)naphthalen-2-yl)oxy)propyl)carbamate 94 7-(3-amino-propoxy)-3-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)-amino)- pyridazin-3-yl)naphthalen-2-ol 95 N-(3-((7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalen-2-yl)oxy)propyl)acetamide 96 7-(3-hydroxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)naphthalen-2-ol 97 7-(3-methoxypropoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)naphthalen-2-ol 98 7-(2-morpholinoethoxy)-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)naphthalen-2-ol 99 3-(6-(piperidin-4-ylmethyl)pyridazin-3-yl)naphthalen-2-ol 100 5-(1H-pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3- yl)phenol 101 3-methoxy-2-(6-(methyl(2,2,6-trimethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5- methyloxazol-2-yl)phenol 102 2-(6-((6S)-6-((S)-1-hydroxyethyl)-2,2-dimethylpiperidin-4-yloxy)pyridazin-3-yl)-5- (1H-pyrazol-1-yl)phenol 103 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2- naphthonitrile 104 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7- (piperidinylmethyl)naphthalen-2-ol 105 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7- (pyrrolidinylmethyl)naphthaien-2-ol 106 1-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalene-2,7-diol 107 1-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalene-2,7-diol 108 7-methoxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalene-2-ol 109 7-methoxy-3-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalen-2-ol 110 7-(3,6-dihydro-2H-pyran-4-yl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)naphthalen-2-ol 111 3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-7-(tetrahydro-2H- pyran-4-yl)naphthalene-2-ol 112 7-(difluoromethyl)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)naphthalen-2-ol 113 7-((4-hydroxy-2-methylbutan-2-yl)oxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)naphthalen-2-ol 114 7-(3-hydroxy-3-methylbutoxy)-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)naphthalen-2-ol 115 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4- yl)benzene-1,3-diol 116 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5- (1H-pyrazol-4-yl)phenol 117 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3- (trifluoromethoxy)phenol 118 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H- pyrazol-4-yl)-3-(trifluoromethoxy)phenol 119 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H-pyrazol-4- yl)-3-(trifluoromethoxy)phenol 120 4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5- (trifluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one 121 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)phenol 122 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5- (5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)phenol 123 3-methoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5- (pyridine-3-yl)phenol 124 5-(1-cyclopentyl-1H-pyrazol-4-yl)-3-methoxy-2-(6-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol 125 3′,5-dimethoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)- (1,1′-biphenyl)-3-ol 126 3-(benzyloxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5- (5-methyloxazol-2-yl)phenol 127 3-ethoxy-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5- methyloxazol-2-yl)phenol 128 3-(cyclopropylmethoxy)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)- pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol 129 2-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H- benzo[d]imidazol-6-ol 130 5-chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol 131 5-(1H-pyrazol-1-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyri dazin-3- yl)phenol 132 3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile 133 2-(6-((2,2-dimethylpiperidin-4-yl)oxy)pyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol 134 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-4- yl)phenol 135 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridin-3-yl)-4-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenol 136 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-3-yl)phenol 137 4-(1H-indol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol 138 4-(cyclopent-1-en-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 139 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-3- yl)phenol 140 4-(4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)pyridin-2-ol 141 4-(4-hydroxy-3-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)-1- methylpyridin-2(1H)-one 142 4-(4-hydroxy-3-(6-((2,2,6,6-tetratnethylpiperidin-4-yl)oxy)pyridazin-3- yl)phenyl)pyridin-2-ol 143 5-(1H-indazol-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol 144 4-chloro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 145 4-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 146 5-fluoro-4-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 147 5-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H- pyrazol-4-yl)phenol 148 5-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H- pyrazol-5-yl)phenol 149 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3- dihydro-1H-inden-1-one 150 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1,4- dihydroindeno[1,2-c]-1H-pyrazol-7-ol 151.sup.1 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3- dihydro-1H-inden-1-one oxime 152 5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H- indene-1,6-diol 153.sup.1 2-amino-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-8H- indeno[1,2-d]thiazol-5-ol 154.sup.1 9-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-8-ol 155 4-hydroxy-3-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-N-((1- methyl-1H-pyrazol-4-yl)methyl)benzamide 156 4-(4-(hydroxymethyl)-1H-pyrazol-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 157 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3- yl)phenol 158 6-(3-(benzyloxy)isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 159 6-(1-(benzyloxy)isoquinolin-7-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 160.sup.1 3-fluoro-5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 161.sup.1 4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetrarnethylpiperidin-4-yl)arnino)pyridazin- 3-yl)phenyl)pyridin-2(1H)-one 162.sup.1 4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenyl)-1-methylpyridin-2(1H)-one 163.sup.1 5-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenyl)-1-methylpyridin-2(1H)-one 164.sup.1 3-fluoro-5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)phenol 165.sup.1 5-chloro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol 166.sup.1 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 167.sup.1 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)phenol 168 5-(5-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 169 5-(3-hydroxy-4-(6-methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)pyridin-2-ol 170 4-(3-hydroxy-4-(6-methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)pyridin-2-ol 171 5-(6-methoxypyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 172 5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)-3-(trifluoromethyl)pyridin-2-ol 173 5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyri dazin-3- yl)phenyl)-1-methylpyridin-2(1H)-one 174 4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)-1-methylpyridin-2(1H)-one 175 5-(2-methoxypyridin-4-yl)-2-(6-( (2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 176 4-(3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)phenyl)pyridin-2-ol 177 5-(6-(dimethylamino)pyridin-3-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyri dazin-3-yl)phenol 178 4-(3-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl)-1- methylpyridin-2(1H)-one 179 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(pyrimidin-5- yl)phenol 180 5-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)pyridin-3-ol 181 1-cyclopropyl-4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenyl)pyridin-2(1H)-one 182 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1,2,3,6- tetrahydropyridin-4-yl)phenol 183 5-(cyclopent-1-en-1-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 184 5-(3,6-dihydro-2H-pyran-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 185 5-(imidazo[1,5-a]pyridin-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 186 5-(imidazo[1,2-a]pyridin-7-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 187 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(2- methylpyridin-4-yl)phenol 188 5-(1H-imidazol-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenol 189 5-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)phenol 190 5-(imidazo[1,2-a]pyrazin-3-yl)-2-(6-(tnethyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 191 2-(6-(methyl(2,2,6,6-tetratnethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5,6,7,8- tetrahydroimidazo[1,2-a]pyrazin-3-yl)phenol 192 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(4-methyl-1H- imidazol-2-yl)phenol 193 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H- imidazol-4-yl)phenol 194 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-methyl-1H- imidazol-5-yl)phenol 195 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(4-nitro-1H- imidazol-2-yl)phenol 196 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(2-methyl-1H- imidazol-4-yl)phenol 197 5-(1,2-dimethyl-1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol 198 1-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-y1)amino)pyridazin-3- yl)phenyl)-1H-pyrazole-4-carboxamide 199 2-(6-((3aR,6aS)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin- 3-yl)-5-(1H-pyrazol-4-yl)phenol 200 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol 201 2-(6-((3aR,6aS)-5-methy1Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yr)pyridazin-3-yl)-5- (1H-pyrazol-4-yl)phenol 202 4-(3-hydroxy-4-(6-(5-methy1Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3- yl)phenyl)-1-methylpyridin-2(1H)-one 203 4-(3-hydroxy-4-(6-((3aR,6aR)-1-methy1Hexahydropyrrolo[3,4-b]pyrrol-5(1H)- yl)pyridazin-3-yl)phenyl)-1-methylpyridin-2(1H)-one 204 2-(6-(2,7-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol 205 4-(4-(6-(2,7-diazaspiro[4.5]decan-2-yl)pyridazin-3-yl)-3-hydroxyphenyl)-1- methylpyridin-2(1H)-one 206 2-(6-(methyl-(2,2,6,6-tetramethylpiperidin-4-yl)-amino)-pyridazin-3-yl)phenol 207 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol 208 6-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol 209 6-(6-((3aR,6aS)-5-methylHexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3- yl)quinolin-7-ol 210 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 7-ol 211 7-(6-(methyl(1,2,2,6,6-pentamethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol 212 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-6-ol 213 7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline-6-ol 214 7-(6-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3- yl)isoquinolin-6-ol 215 1-cyclopropyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 216 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinoline-1,6- diol 217 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinoline-1-carbonitrile 218 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)isoquinolin-7-ol 219 8-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-7-ol 220 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol 221 2-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol 222 3-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 7-ol 223 3-bromo-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 7-ol 224 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoline-3-carbonitrile 225 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(1-methyl-1H- imidazol-4-yl)quinolin-7-ol 226.sup.1 3-(1H-imidazol-1-yl)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin- 3-yl)quinolin-7-ol 227 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-3,7-diol 228 3-ethyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yr)amino)pyridazin-3-yl)quinolin- 7-ol 229 3-isopropyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 230 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolm-2(1H)-one 231.sup.1 7-hydroxy-1-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-2(1H)-one 232 4-methoxy-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 233 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- (pyrrolidin-1-yl)quinolin-7-ol 234 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- morpholinoquinolin-7-ol 235 4-(dimethylamino)-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)quinolin-7-ol 236 4-ethoxy-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 237 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1- methyl-1H-pyrazol-4-yl)quinolin-7-ol 238.sup.1 4-methoxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-6-ol 239.sup.1 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoxalin-6-ol 240 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(tetrahydro-2H- pyran-4-yl)quinolin-7-ol 241 3-chloro-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol 242 3-bromo-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol 243 3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol 244 5-bromo-3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-6-ol 245 6-hydroxy-1-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-4(1H)-one 246 2,3-dimethyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-6-ol 247 2-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoxalin-6-ol 248 3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoxalin-6-ol 249 4-methoxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 250 4-(azetidin-1-yl)-2-methyl-6-(6-(methyl(2,2,6,6-tetraniethylpiperidin-4- yl)amino)pyridazin-3-yl)quinolin-7-ol 251 7-hydroxy-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolone-4-carbonitrile 252 4-cyclopropyl-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)-quinolin-7-ol 253 4-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)quinolin-7-ol 254.sup.1 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- (tetrahydro-2H-pyran-4-yl)quinolin-7-ol 255 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- (oxetan-3-yl)quinolin-7-ol 256.sup.1 4-(dimethylamino)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)-quinolin-7-ol 257 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinazolin-4(1H)-one 258 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinazolin-7-ol 259 7-hydroxy-1-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)-3,4-dihydroquinolin-2(1H)-one 260 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinazolin-7-ol 261 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinoline-1-carbonitrile 262 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoline-2-carbonitrile 263 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-2-carbonitrile 264 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinoline-1-carboxamide 265 7-hydroxy-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-2-carboxamide 266 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoline-2-carboxamide 267 methyl 6-hydroxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoline-2-carboxylate 268 6-hydroxy-7-(6-(piperazin-1-yl)pyridazin-3-yl)quinoline-2-carbonitrile 269 7-hydroxy-6-(6-(piperazin-1-yl)pyridazin-3-yl)quinoline-2-carbonitrile 270 7-(6-(piperazin-1-yl)pyridazin-3-yl)isoquinolin-6-ol 271 7-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)quinolin-6-ol 272 l-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- y l)i soquinoli n-7-ol 273 1-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperi din-4-y l)amino)pyri dazin-3- yl)isoquinolin-6-ol 274 1,3-dimethyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 275 7-hydroxy-3-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinoline-1-carbonitrile 276 1-amino-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 277 7-hydroxy-1,3-dimethyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)quinazoline-2,4(1H,3H)-dione 278 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)benzo[d]oxazol-2(3H)-one 279 2-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2H- indazol-6-ol 280 1-methyl-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-1H- indazol-6-ol 281.sup.1 6-hydroxy-2-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-1(2H)-one 282 2-ethyl-6-hydroxy-7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)isoquinolin-1(2H)-one 283 1-ethoxy-7-(6-(methyl2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 284 7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)isoquinoline-1,6-diol 285 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-pyridazin-3-yl)-3- phenylisoquinolin-6-ol 286 3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 287 3-cyclopropyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 288 3-isopropyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-6-ol 289 3-propyl-7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-pyridazin-3-yl)isoquinolin-6-ol 290 3-isopropyl-7-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-pyridazin-3-yl)isoquinolin-6- ol 291 3-methyl-7-(6-(piperazin-1-yl)pyridazin-3-yl)isoquinolin-6-ol 292 6-(3-(benzyloxy)isoquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 293 3-chloro-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 7-ol 294 3-isopropyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 295 3-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinoxalin-6-ol 296 4-chloro-2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol 297 4-chloro-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol 300 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin-6-ol 301 5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 302 6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen- 2-ol 303 5-(2-methoxyquinolin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazol-2-amine 304 5-(3-methoxy-naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazol-2-amine 305 5-(2-methoxy-4-(1H-pyrazol-1yl)phenyl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 306 5-(2-tnethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 307 5-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 308 4-(3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 309 5-(3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)pyridin-2-ol 310 5-(3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 311 N-methyl-5-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 312 1-methyl-4-(4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-3-(trifluoromethoxy)phenyl)pyridin-2(1H)-one 313 5-(4-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 314 5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 315 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4,-thiadiozol-2-yl-5-(1- methyl-1H-pyrazol-4-yl)phenol 316 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4,-thiadiozol-2-yl-5-(1H- pyrazol-1-yl)phenol 317 5-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 318 4-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 319 5-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)pyridin-2-ol 320 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)naphthalene-2,7-diol 321 3-(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol-2- yl)naphthalene-2,7-diol 322.sup.1 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen- 2-ol 323 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2- ol 324 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-4-(1H- pyrazol-1-yl)phenol 325 5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 326 3-chloro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)- 5-(1-methyl-1H-pyrazol-4-yl)phenol 327 5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)- l,3,4-thiadiazol-2-amine 328 3-methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-methyloxazol-2-yl)phenol 329 2-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,3,4- thiadiazole 330 2-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenol 331 5-(7-methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazole-2-amine 332 6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-7- ol 333 3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzonitrile 334 3-fluoro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzonitrile 335 methyl-3-fluoro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol- 2-yl)benzoate 336 5-(2-methoxy-4-(3-(methylamino)-1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 337 7-methoxy-6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinoline-2-carbonitrile 338 4-(3-methoxy-4-(5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin-2(1H)-one 339 4-(3-chloro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl(phenyl)-1-methylpyridin-2(1H)-one 340 5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 341 5-(2-chloro-4-(4,5,6,7-tetrahydropyrazolo[l,5-a]pyridin-3-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 342.sup.1 N-methyl-5-(5-(1-methyl-l H-pyrazol-4-yl)pyridin-2-yl)-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 343 2-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-((2,2,6,6-tetramethylpiperidin-4- yl)oxy-1,3,4-thiadiazole 344 5-(2-chloro-4-(6-methoxypyridin-3-yl)phenyl)-N-niethyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 345 5-(4-(6-aminopyridin-3-yl)-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 346 5-(2-fluoro-4-(3-methyl-1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 347 5-(2-fluoro-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 348 5-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 349 5-(2,3-difluoro-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 350 5-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 351 5-(2,5-difluoro-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 352 5-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 353 2-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 354 5-(2-chloro-5-fluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 355 5-(3-fluoro-5-(1H-pyrazol-4-yl)pyridin-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 356 5-(4-(2-aminopyrimidin-4-yl)-2-chlorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 357 5-(5-(2-aminopyrimidin-4-yl)-2-chlorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 358 5-(4-(2,4-dimethylthiazol-5-yl)-2,5-difluorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 359 5-(4-(2,4-dimethylthiazol-5-yl)-2,3-difluorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 360 4-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(trifluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one 361 5-(2-fluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 362 2-(2-fluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5- methylHexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 363 5-(2,3-difluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 364 6-methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-3,4-dihydroisoquinolin-1-(2H)-one 365 5-(2-chloro-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 366 5-(2-chloro-4-(1H-1,2,3-triazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 367 5-(2-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 368 5-(2-chloro-4-(1H-1,2,4-triazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 369 5-(4-(3-amino-1H-pyrazol-1-yl)-2-chlorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 370 2-(2-chloro-4-(1H-imidazol-1-yl)phenyl)-5-((3aR,6aS)-5- methylhexahydropyrrolo[3,4c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 371 5-(2-chloro-4-(1H-imidazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 372 5-(2-fluoro-4-(1H-imidazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 373 5-(2-methoxy-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 374 5-(4-(2,4-dimethylthiazol-5-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 375 5-(2-methoxy-4-(pyridin-3-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 376 5-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 377 5-(2-methoxy-4-(2-methoxypyridin-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 378 5-(2-methoxy-4-(6-methoxypyridin-3-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 379 2-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl(-1,3,4-thiadiazole 380 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl(-1,3,4-thiadiazole 381 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aR)-1-methylhexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)-1,3,4-thiadiazole 382 1-(4-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)morpholin-2-yl)- N,N-dimethylmethanamine 383 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-(2-methyl-2,7-diazaspiro[4.5]decan-7-yl(- 1,3,4-thiadiazole 384 2-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole 385 2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,6-diazaspiro[3.5]nonan-2-yl)- 1,3,4-thiadiazole 386 2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl(- 1,3,4-thiadiazole 387 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H- pyrazol-1-yl)phenol 388 5-(3-chloro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl(phenyl(pyridin-2(1H)-one 389 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(3- (methylamino)-1H-pyrazol-1-yl)phenol 390 3-fluoro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5- (1H-pyrazol-4-yl)phenol 391 3,4-difluoro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4-yl)phenol 392 6-hydroxy-5-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-2,3-dihydro-1H-inden-1-one 393 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H- pyrazol-4-yl)phenol 394 2-(5-(2,6-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4- yl)phenol 395 2-(5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4- yl)phenol 396.sup.1 3-fluoro-2-(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4-yl)phenol 397 3-chloro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)- 5-(1H-pyrazol-4-yl(phenol 398 2-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-((2,2,6,6-tetramethylpiperidin-4- yl)methyl)-1,3,4-thiadiazole 399 2-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4- thiadiazole 400 2-(5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-3-fluoro-5-(1H-pyrazol-4- yl)phenol 401 4-methoxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4- thiadiazol-2-yl)quinolin-2(1H)-one 402 4-hydroxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4- thiadiazol-2-yl)quinolin-2(1H)-one 403 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin- 2(1H)-one 404 1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinolin-2(1H)-one 405.sup.1 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1,3,4-thiadiazole 406.sup.1 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[4.5]decan-2-yl)-1,3,4- thiadiazole 407.sup.1 (R)-(4-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)piperazin-2- yl)methanol 408 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzo[b]thiophene-5-carbonitrile 409 5-(3-chlorobenzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 410 5-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 411.sup.1 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl(methyl)amino]pyridazin-3-yl}-5-(1H- pyrazol-4-yl)phenol 412.sup.1 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 413.sup.1 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3- yl}phenol 414 5-(1-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 415.sup.1 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 416 5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]pyridazin-3-yl}phenol 417 5-(1H-imidazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 418 5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 419.sup.1 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H- pyrazol-1-yl)phenol 420 6-[2-methoxy-4-(4-nitro-1H-pyrazol-l-yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine 421 5-(4-amino-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 422.sup.1 2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 423 5-(4-nitro-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 424.sup.1 5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol 425.sup.1 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 426.sup.1 2-{6-[methyl(piperidin-4-yl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol 427.sup.1 2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 428.sup.1 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazin-3-amine 429.sup.1 2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 430.sup.1 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazin-3-amine 431.sup.1 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 432 2-[6-(piperidin-4-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 433.sup.1 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino]pyridazin-3-yl(-5-(1H-pyrazol-4- yl)phenol 434.sup.1 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine 435 3-[4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 436.sup.1 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol 437.sup.1 3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 438 3-[4-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 439.sup.1 2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 440 3-fluoro-4-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol 441 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-1-yl)phenol 442 N-methyl-6-(2-methyl-2H-indazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin- 3-amine 443 2-methyl-5-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}-2H-indazole 444 3-(4-chloro-2-methoxyphenyl)-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 445 N-methyl-6-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 446 6-{6-[(2,2,6,6-tetramethylpiperidin-4-yl(oxy]pyridazin-3-yl}imidazo[1,2-a]pyridine 447 3-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl(oxy]pyridazine 448.sup.1 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 449 3-[5-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl(oxy]pyridazine 450.sup.1 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 451 5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazin-3-yl(phenol 452 6-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 453 3-methoxy-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 454 3-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl(oxy]pyridazine 455 4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}benzene-1,3-diol 456.sup.1 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 457 2-(1H-pyrazol-4-yl)-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}pyrimidin-5-amine 458.sup.1 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 459 2-[6-(2,6-diazaspiro[3.4]oct-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 460.sup.1 3-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4- yl)pyridin-2-ol 461 6-(1H-pyrazol-4-yl)-3-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}pyridin-2-ol 462.sup.1 N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine 463.sup.1 N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol-4-yl(phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine 464.sup.1 3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine and 465.sup.1 6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine
(96) wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(97) In another aspect, the compound of Formula (I) or a form thereof used in a method disclosed herein is a compound selected from the group consisting of:
(98) TABLE-US-00036 Cpd Name 411.sup.1 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-y1(methyl)amino]pyridazin-3-yl-5-(1H- pyrazol-4-yl)phenol 412.sup.1 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 413.sup.1 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3- yl}phenol 414 5-(1-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 415.sup.1 2-[6-((1R,5S)-8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 416 5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]pyridazin-3-yl}phenol 417 5-(1H-imidazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 418 5-(5-methyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 419.sup.1 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H- pyrazol-1-yl)phenol 420 6-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine 421 5-(4-amino-1H-pyrazol-1-yl)-2-[6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 422.sup.1 2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4- yl)phenol 423 5-(4-nitro-1H-pyrazol-1-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}phenol 424.sup.1 5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol 425.sup.1 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 426.sup.1 2-{6-[methyl(piperidin-4-yl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol 427.sup.1 2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 428.sup.1 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)pyridazin-3-amine 429.sup.1 2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 430.sup.1 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-y1)pyridazin-3-amine 431.sup.1 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 432 2-[6-(piperidin-4-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 433.sup.1 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino]pyridazin-3-yl}-5-(1H-pyrazol-4- yl)phenol 434.sup.1 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine 435 3-[4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 436.sup.1 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol 437.sup.1 3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 438 3-[4-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 439.sup.1 2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 440 3-fluoro-4-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}phenol 441 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-1-yl)phenol 442 N-methyl-6-(2-methyl-2H-indazol-5-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin- 3-amine 443 2-methyl-5-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}-2H-indazole 444 3-(4-chloro-2-methoxyphenyl)-6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazine 445 N-methyl-6-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 446 6-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}imidazo[1,2-a]pyridine 447 3-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 448.sup.1 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 449 3-[5-(1-methyl-1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 450.sup.1 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 451 5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazin-3-yl}phenol 452 6-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 453 3-methoxy-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}phenol 454 3-[2-methoxy-4-(4-nitro-1H-pyrazol-1-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 455 4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3-yl}benzene-1,3-diol 456.sup.1 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine 457 2-(1H-pyrazol-4-yl)-4-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}pyrimidin-5-amine 458.sup.1 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)pheny1]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine 459 2-[6-(2,6-diazaspiro[3.4]oct-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol 460.sup.1 3-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4- yl)pyridin-2-ol 461 6-(1H-pyrazol-4-yl)-3-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]pyridazin-3- yl}pyridin-2-ol 462.sup.1 N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine 463.sup.1 N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine 464.sup.1 3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine and 465.sup.1 6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine
(99) wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(100) In another aspect, the compound of Formula (I) or a form thereof used in a method disclosed herein is a compound salt selected from the group consisting of:
(101) TABLE-US-00037 Cpd Name 32 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- (trifluoromethyl)phenol hydrochloride 53 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4-(1H-pyrazol-1- yl)phenol hydrochloride 65 2-(6-piperazin-1-yl-pyridazin-3-yl)-5-1H-pyrazol-1-yl-phenol hydrochloride 82 3-(6-(piperazin-1-yl)pyridazin-3-yl)naphthalene-2,7-diol trifluoroacetate 86 3-(6-(1,2,3,6-tetrahydropyridin-4-y1)pyridazin-3-yl)naphthalene-2,7-diol trifluoroacetate 88 3-(6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol trifluoroacetate 89 3-(6-(piperidin-4-yl)pyridazin-3-yl)naphthalene-2,7-diol trifluoroacetate 151 6-hydroxy-5-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-2,3- dihydro-1H-inden-1-one oxime hydrochloride 153 2-amino-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-y1)-8H- indeno[1,2-d]thiazol-5-ol hydrochloride 154 9-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5,6- dihydroimidazo[5,1-a]isoquinolin-8-ol hydrochloride 160 3-fluoro-5-(2-methoxypyridin-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)pyridazin-3-yl)phenol hydrochloride 161 4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)pyridin-2(1H)-one hydrochloride 162 4-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)-1-methylpyridin-2(1H)-one hydrochloride 163 5-(3-fluoro-5-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenyl)-1-methylpyridin-2(1H)-one hydrochloride 164 3-fluoro-5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3- yl)phenol hydrochloride 165 5-ch1oro-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)phenol hydrochloride 166 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1H- pyrazol-4-yl)phenol hydrochloride 167 3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)phenol hydrochloride 226 3-(1H-imidazol-1-yl)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-7-ol hydrochloride 227 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoline-3,7-diol formate 231 7-hydroxy-1-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)quinolin-2(1H)-one hydrochloride 238 4-methoxy-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinolin- 6-ol formate 239 7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)quinoxalin-6-ol hydrochloride 254 2-methyl-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-4- (tetrahydro-2H-pyran-4-yl)quinolin-7-ol formate 256 4-(dimethylamino)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)- quinolin-7-ol formate 281 6-hydroxy-2-methyl-7-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3- yl)isoquinolin-1(2H)-one hydrochloride 322 3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen- 2-ol hydrobromide 342 N-methyl-5-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine hydrochloride 396 3-fluoro-2-(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol-2-yl)- 5-(1H-pyrazol-4-yl)phenol dihydrochloride 405 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1,3,4-thiadiazole hydrochloride 406 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[4.5]decan-2-yl)-1,3,4- thiadiazole hydrochloride 407 (R)-(4-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)piperazin-2- yl)methanol hydrochloride 411 2-{6-[8-azabicyclo[3.2.1]oct-3-yl(methyl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4- yl)phenol hydrochloride 412 2-[6-(8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 413 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3- yl}phenol hydrochloride 415 2-[6-(8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 419 2-(6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H- pyrazol-1-yl)phenol dihydrochloride 422 2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride 424 5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol trihydrochloride 425 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride 426 2-{6-[methyl(piperidin-4-yl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 427 2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 428 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine tetrahydrochloride 429 2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 430 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine hydrochloride 431 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine trihydrochloride 433 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino]pyridazin-3-yl}-5-(1H-pyrazol-4- yl)phenol hydrochloride 434 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride 436 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol trihydrochloride 437 3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 439 2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 448 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 450 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 456 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine trihydrochloride 458 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine trihydrochloride 460 3-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4- yl)pyridin-2-ol hydrochloride 462 N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine hydrochloride 463 N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine hydrochloride 464 3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride and 465 6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride
(102) wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(103) In another aspect, the compound of Formula (I) used in a method disclosed herein is a compound salt selected from the group consisting of:
(104) TABLE-US-00038 Cp Name 411 2-{6-[8-azabicyclo[3.2.1]oct-3-yl(methyl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4- yl)phenol hydrochloride 412 2-[6-(8-azabicyclo[3.2.1]oct-3-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 413 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3- yl}phenol hydrochloride 415 2-[6-(8-azabicyclo[3.2.1]oct-3-yloxy)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 419 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-5-(4-nitro-1H- pyrazol-1-yl)phenol dihydrochloride 422 2-[6-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride 424 5-(1H-pyrazol-4-yl)-2-[6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]phenol trihydrochloride 425 2-[6-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol trihydrochloride 426 2-{6-[methyl(piperidin-4-yl)amino]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 427 2-[6-(piperidin-4-ylamino)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 428 6-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine tetrahydrochloride 429 2-[6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 430 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine hydrochloride 431 3-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine trihydrochloride 433 2-{6-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-ylamino]pyridazin-3-yl}-5-(1H-pyrazol-4- yl)phenol hydrochloride 434 6-[2-methoxy-6-(1H-pyrazol-4-yl)pyridin-3-yl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride 436 2-{6-[(2,6-dimethylpiperidin-4-yl)oxy]pyridazin-3-yl}-5-(1H-pyrazol-4-yl)phenol trihydrochloride 437 3-[2-fluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 439 2-[6-(2,7-diazaspiro[3.5]non-2-yl)pyridazin-3-yl]-5-(1H-pyrazol-4-yl)phenol tetrahydrochloride 448 3-[5-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 450 3-[4-(1H-pyrazol-4-yl)thiophen-2-yl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride 456 6-[2-chloro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)pyridazin-3-amine trihydrochloride 458 3-[2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine trihydrochloride 460 3-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyridazin-3-yl}-6-(1H-pyrazol-4- yl)pyridin-2-ol hydrochloride 462 N,2,2,6,6-pentamethyl-N-{5-[3-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine hydrochloride 463 N,2,2,6,6-pentamethyl-N-{5-[4-(1H-pyrazol-4-yl)phenoxy]-1,3,4-thiadiazol-2- yl}piperidin-4-amine hydrochloride 464 3-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-6-[(2,2,6,6-tetramethylpiperidin-4- yl)oxy]pyridazine hydrochloride and 465 6-[2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)pyridazin-3-amine hydrochloride
(105) wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Terminology
(106) As used herein, the term “C.sub.1-4alkyl” generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a straight or branched chain configuration, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like. In some aspects, C.sub.1-4alkyl includes C.sub.1-3alkyl, C.sub.1-2alkyl, and the like. A C.sub.1-4alkyl radical may be optionally substituted where allowed by available valences.
(107) As used herein, the term “C.sub.2-6alkenyl” generally refers to partially unsaturated hydrocarbon radicals having from two to five carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, without limitation, ethenyl, allyl, propenyl and the like. In some aspects, C.sub.2-6alkenyl includes C.sub.2-4alkenyl, C.sub.2-3alkenyl, and the like. A C.sub.2-6alkenyl radical may be optionally substituted where allowed by available valences.
(108) As used herein, the term “C.sub.1-4alkoxy” generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a straight or branched chain configuration of the formula: —O—C.sub.1-4alkyl, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. In some aspects, C.sub.1-4alkoxy includes C.sub.1-3alkoxy, C.sub.1-2alkoxy and the like. A C.sub.1-4alkoxy radical may be optionally substituted where allowed by available valences.
(109) As used herein, the term “C.sub.3-14cycloalkyl” generally refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthalenyl and the like. In some aspects, C.sub.3-4cycloalkyl includes C.sub.3-10cycloalkyl, C.sub.3-8cycloalkyl, C.sub.3-7cycloalkyl, C.sub.5-8cycloalkyl, C.sub.9-10cycloalkyl and the like. A C.sub.3-14cycloalkyl radical may be optionally substituted where allowed by available valences.
(110) As used herein, the term “C.sub.3-14cycloalkenyl” generally refers to a partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon radical having one or more chemically stable carbon-carbon double bonds therein, including, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like. In some aspects, C.sub.3-14cycloalkenyl includes C.sub.3-7cycloalkenyl, C.sub.3-8cycloalkenyl, C.sub.5-8cycloalkenyl, C.sub.3-10cycloalkenyl and the like. A C.sub.3-14cycloalkenyl radical may be optionally substituted where allowed by available valences.
(111) As used herein, the term “aryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An aryl radical may be optionally substituted where allowed by available valences.
(112) As used herein, the term “heteroaryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, without limitation, furanyl, thienyl (also referred to as thiophenyl), pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, 9H-purinyl, quinoxalinyl, isoindolyl, quinolinyl, isoquinolinyl, quinazolinyl, acridinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazo[5,1-a]isoquinolinyl, 1,4-dihydroindeno[1,2-c]-1H-pyrazolyl, 2,3-dihydro-1H-inden-1-one, 2,3-dihydro-1H-indenyl, 3,4-dihydroquinolin-2(H)-one, 5,6-dihydroimidazo[5,1-a]isoquinolinyl, 8H-indeno[1,2-d]thiazolyl, benzo[c][1,2,5]oxadiazolyl, benzo[d]oxazol-2(3H)-one, quinolin-2(1H)-one, quinazolin-4(1H)-one, quinazoline-2,4(1H,3H)-dione, benzo-[d]oxazolyl, pyrazolo[1,5-a]pyridinyl, and the like. A heteroaryl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
(113) As used herein, the term “heterocyclyl” generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, without limitation, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl, pyrazolinyl, pyrazolidinyl, dihydroimidazolyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, dihydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydro-pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1,4,5,6-tetrahydropyrimidinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl, tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl, dihydro-benzooxazolyl, 2,3-dihydrobenzo[d]oxazolyl, tetrahydro-benzooxazolyl, dihydro-benzooxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, tetrahydro-benzooxazinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxanyl, dihydro-purinyl, tetrahydro-purinyl, dihydro-quinolinyl, tetrahydro-quinolinyl, 1,2,3,4-tetrahydroquinolinyl, dihydro-isoquinolinyl, 3,4-dihydroisoquinolin-(1H)-yl, tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, dihydro-quinazolinyl, tetrahydro-quinazolinyl, dihydro-quinoxalinyl, tetrahydro-quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-imidazolyl, tetrahydro-2H-pyranyl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-(4aH)-yl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, (cis)-octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-1H-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9-tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3-dihydro-1H-pyrrolo[1,2-a]indolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4S,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, 1,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-1H-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptenyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.0]hexanyl, (1R,5S)-3-azabicyclo[3.1.0]hexanyl, (1S,5R)-3-azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 3,6-diazabicyclo[3.2.1]octyl, 1,4-dihydroindeno[1,2-c]pyrazolyl, dihydropyranyl, dihydropyridinyl, dihydroquinolinyl, 8H-indeno[1,2-d]thiazolyl, tetrahydroimidazo[1,2-a]pyridinyl, pyridin-2(1H)-one, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl and the like. A heterocyclyl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
(114) As used herein, the term “C.sub.2-4alkenyl-amino-carbonyl” refers to a radical of the formula: —C(═O)—NH—C.sub.2-4alkenyl.
(115) As used herein, the term “C.sub.1-4alkoxy-C.sub.1-4alkoxy” refers to a radical of the formula: —O—C.sub.1-4alkyl-O—C.sub.1-4alkyl.
(116) As used herein, the term “C.sub.1-4alkoxy-carbonyl” refers to a radical of the formula: —C(═O)—O—C.sub.1-4alkyl.
(117) As used herein, the term “C.sub.1-4alkoxy-carbonyl-amino” refers to a radical of the formula: —NH—C(═O)—O—C.sub.1-4alkyl.
(118) As used herein, the term “C.sub.1-4alkoxy-carbonyl-amino-C.sub.1-4alkoxy” refers to a radical of the formula: —O—C.sub.1-4alkyl-NH—C(═O)—O—C.sub.1-4alkyl.
(119) As used herein, the term “C.sub.1-4alkyl-C.sub.1-4alkoxy” refers to a radical of the formula: —O—C.sub.1-4alkyl-C.sub.1-4alkyl.
(120) As used herein, the term “C.sub.1-4alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-4alkyl.
(121) As used herein, the term “(C.sub.1-4alkyl).sub.2-amino” refers to a radical of the formula: —N(C.sub.1-4alkyl).sub.2.
(122) As used herein, the term “C.sub.1-4alkyl-amino-C.sub.1-4alkoxy” refers to a radical of the formula: —O—C.sub.1-4alkyl-NH—C.sub.1-4alkyl.
(123) As used herein, the term “(C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkoxy” refers to a radical of the formula: —O—C.sub.1-4alkyl-N(C.sub.1-4alkyl).sub.2.
(124) As used herein, the term “C.sub.1-4alkyl-amino-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-NH—C.sub.1-4alkyl.
(125) As used herein, the term “(C.sub.1-4alkyl).sub.2-amino-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-N(C.sub.1-4alkyl).sub.2.
(126) As used herein, the term “C.sub.1-4alkyl-amino-carbonyl” refers to a radical of the formula: —C(═O)—NH—C.sub.1-4alkyl.
(127) As used herein, the term “(C.sub.1-4alkyl).sub.2-amino-carbonyl” refers to a radical of the formula: —C(═O)—N(C.sub.1-4alkyl).sub.2.
(128) As used herein, the term “C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-C(═O)—NH—C.sub.1-4alkyl.
(129) As used herein, the term “(C.sub.1-4alkyl).sub.2-amino-carbonyl-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-C(═O)—N(C.sub.1-4alkyl).sub.2.
(130) As used herein, the term “C.sub.1-4alkyl-carbonyl” refers to a radical of the formula: —C(═O)—C.sub.1-4alkyl.
(131) As used herein, the term “C.sub.1-4alkyl-carbonyl-amino” refers to a radical of the formula: —NH—C(═O)—C.sub.1-4alkyl.
(132) As used herein, the term “C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkoxy” refers to a radical of the formula: —O—C.sub.1-4alkyl-NH—C(═O)—C.sub.1-4alkyl.
(133) As used herein, the term “C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-NH—C(═O)—C.sub.1-4alkyl.
(134) As used herein, the term “amino” refers to a radical of the formula: —NH.sub.2.
(135) As used herein, the term “amino-C.sub.1-4alkoxy” refers to a radical of the formula: —O—C.sub.1-4alkyl-NH.sub.2.
(136) As used herein, the term “amino-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-NH.sub.2.
(137) As used herein, the term “amino-carbonyl” refers to a radical of the formula: —C(═O)—NH.sub.2.
(138) As used herein, the term “cyano” refers to a radical of the formula: —CN.
(139) As used herein, the term “C.sub.3-7cycloalkyl-C.sub.1-4alkoxy” refers to a radical of the formula: —O—C.sub.1-4alkyl-C.sub.3-7cycloalkyl.
(140) As used herein, the term “halo-C.sub.1-4alkoxy” refers to a radical of the formula: —O—C.sub.1-4alkyl-halo, wherein C.sub.1-4alkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some aspects, halo-C.sub.1-4alkoxy includes halo-C.sub.1-6alkoxy, halo-C.sub.1-4alkoxy and the like.
(141) As used herein, the term “halo-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-halo, wherein C.sub.1-4alkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some aspects, halo-C.sub.1-4alkyl includes halo-C.sub.1-4alkyl, halo-C.sub.1-4alkyl and the like.
(142) As used herein, the term “heteroaryl-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-heteroaryl.
(143) As used herein, the term “heteroaryl-C.sub.1-4alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-4alkyl-heteroaryl.
(144) As used herein, the term “heteroaryl-C.sub.1-4alkyl-amino-carbonyl” refers to a radical of the formula: —C(═O)—NH—C.sub.1-4alkyl-heteroaryl.
(145) As used herein, the term “heteroaryl-C.sub.1-4alkyl-amino-carbonyl-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-C(═O)—NH—C.sub.1-4alkyl-heteroaryl.
(146) As used herein, the term “heteroaryl-C.sub.1-4alkyl-carbonyl-amino” refers to a radical of the formula: —NH—C(═O)—C.sub.1-4alkyl-heteroaryl.
(147) As used herein, the term “heteroaryl-C.sub.1-4alkyl-carbonyl-amino-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-NH—C(═O)—C.sub.1-4alkyl-heteroaryl.
(148) As used herein, the term “heterocyclyl-C.sub.1-4alkoxy” refers to a radical of the formula: —C.sub.1-4alkoxy-heterocyclyl.
(149) As used herein, the term “heterocyclyl-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-heterocyclyl.
(150) As used herein, the term “hydroxyl” refers to a radical of the formula: —OH.
(151) As used herein, the term “hydroxyl-C.sub.1-4alkoxy” refers to a radical of the formula: —O—C.sub.1-4alkyl-OH, wherein C.sub.1-4alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxy radicals.
(152) As used herein, the term “hydroxyl-C.sub.1-4alkyl” refers to a radical of the formula: —C.sub.1-4alkyl-OH, wherein C.sub.1-4alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxy radicals.
(153) As used herein, the term “hydroxyl-C.sub.1-4alkyl-amino” refers to a radical of the formula: —NH—C.sub.1-4alkyl-OH, wherein C.sub.1-4alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
(154) As used herein, the term “hydroxyl-imino” refers to the ═NOH radical of the formula: C(═NOH).
(155) As used herein, the term “oxo” refers to the radical of the formula: C═O.
(156) As used herein, the term “phenyl-C.sub.1-4alkoxy” refers to a radical of the formula: —C.sub.1-4alkoxy-phenyl.
(157) As used herein, the term “substituent” means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., “oxo” or “═O”) as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure of Formula (I). A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.
(158) As used herein, the term “and the like,” with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, isomers (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.
(159) For the purposes of this description, where one or more substituent variables for a compound of Formula (I) or a form thereof encompass functionalities incorporated into a compound of Formula (I), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.
(160) As used herein, the terms “independently selected,” or “each selected” refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I), the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Further, the use of a generic substituent variable on any formula or structure for a compound described herein is understood to include the replacement of the generic substituent with species substituents that are included within the particular genus, e.g., aryl may be replaced with phenyl or naphthalenyl and the like, and that the resulting compound is to be included within the scope of the compounds described herein.
(161) As used herein, the terms “each instance of” or “in each instance, when present,” when used preceding a phrase such as “ . . . C.sub.3-14cycloalkyl, C.sub.3-14cycloalkyl-C.sub.1-4alkyl, aryl, aryl-C.sub.1-4alkyl, heteroaryl, heteroaryl-C.sub.1-4alkyl, heterocyclyl and heterocyclyl-C.sub.1-4alkyl,” are intended to refer to the C.sub.3-14cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each are present either alone or as a substituent.
(162) As used herein, the term “optionally substituted” means optional substitution with the specified substituent variables, groups, radicals or moieties.
(163) Compound Forms
(164) As used herein, the term “form” means a compound of Formula (I) having a form selected from the group consisting of a free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
(165) In certain aspects described herein, the form of the compound of Formula (I) is a free acid, free base or salt thereof.
(166) In certain aspects described herein, the form of the compound of Formula (I) is a salt thereof.
(167) In certain aspects described herein, the form of the compound of Formula (I) is an isotopologue thereof.
(168) In certain aspects described herein, the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer or diastereomer thereof.
(169) In certain aspects described herein, the form of the compound of Formula (I) is a tautomer thereof.
(170) In certain aspects described herein, the form of the compound of Formula (I) is a pharmaceutically acceptable form.
(171) In certain aspects described herein, the compound of Formula (I) or a form thereof is isolated for use.
(172) As used herein, the term “isolated” means the physical state of a compound of Formula (I) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.
(173) As used herein, the term “protected” means that a functional group in a compound of Formula (I) or a form thereof is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. In certain instances, the protecting group may also be a polymer resin, such as a Wang resin or a 2-chlorotrityl-chloride resin. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. It will also be appreciated by those skilled in the art, although such protected derivatives of compounds described herein may not possess pharmacological activity as such, they may be administered to a subject and thereafter metabolized in the body to form compounds described herein which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All prodrugs of compounds described herein are included within the scope of the use described herein.
(174) As used herein, the term “prodrug” means a form of an instant compound (e.g., a drug precursor) that is transformed in vivo to yield an active compound of Formula (I) or a form thereof. The transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
(175) In one example, when a compound of Formula (I) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another example, when a compound of Formula (I) or a form thereof contains a hydroxyl functional group, a prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl or a phosphonate ester and the like. In another example, when a compound of Formula (I) or a form thereof contains an amine functional group, a prodrug form can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of compounds of Formula (I) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters and mono-, di- or triphosphate esters or alkyl substituents, where appropriate. As described herein, it is understood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula (I) or a form thereof as a prodrug.
(176) One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to embrace both solvated and unsolvated forms.
(177) As used herein, the term “solvate” means a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, “solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
(178) As used herein, the term “hydrate” means a solvate wherein the solvent molecule is water.
(179) The compounds of Formula (I) can form salts, which are intended to be included within the scope of this description. Reference to a compound of Formula (I) or a form thereof herein is understood to include reference to salt forms thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) or a form thereof contains both a basic moiety, such as, without limitation an amine moiety, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein.
(180) The term “pharmaceutically acceptable salt(s)”, as used herein, means those salts of compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of the Formula (I) may be formed, for example, by reacting a compound of Formula (I) or a form thereof with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
(181) Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. In certain aspects, acid addition salts may include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. Certain aspects of acid addition salts may further include chloride, dichloride, trichloride, bromide, acetate, formate or trifluoroacetate salts.
(182) Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
(183) Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts.
(184) All such acid salts and base salts are intended to be included within the scope of pharmaceutically acceptable salts as described herein. In addition, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this description.
(185) Compounds of Formula (I) and forms thereof, may further exist in a tautomeric form. All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formula (I) or a form thereof as described herein.
(186) The compounds of Formula (I) or a form thereof may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. The present description is intended to include all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures.
(187) The compounds described herein may include one or more chiral centers, and as such may exist as racemic mixtures (R'S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In one aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will recognize, when more than one chiral center is present, the compounds described herein may also exist as a (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.
(188) As used herein, the term “substantially pure” refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.
(189) In one aspect of the description, a compound of Formula (I) or a form thereof is a substantially pure (S) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
(190) In another aspect provided herein are compounds of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib) for use in the methods described herein:
(191) In one aspect of the description, a compound of Formula (I) or a form thereof is a substantially pure (R) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
(192) In another aspect provided herein are compounds of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib) for use in the methods described herein:
(193) As used herein, a “racemate” is any mixture of isometric forms that are not “enantiomerically pure”, including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20.
(194) In another aspect provided herein are compounds of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib) for use in the methods described herein:
(195) In addition, the present description embraces all geometric and positional isomers. For example, if a compound of Formula (I) or a form thereof incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the description. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this description.
(196) In another aspect provided herein are compounds of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib) for use in the methods described herein:
(197) All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this description, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra.
(198) In another aspect provided herein are compounds of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib) for use in the methods described herein:
(199) The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the instant compounds.
(200) In another aspect provided herein are compounds of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib) for use in the methods described herein:
(201) The term “isotopologue” refers to isotopically-enriched compounds described herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, .sup.35Cl and .sup.36Cl, respectively, each of which are also within the scope of this description.
(202) In another aspect provided herein are compounds of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib) for use in the methods described herein:
(203) Certain isotopically-enriched compounds described herein (e.g., those labeled with .sup.3H and .sup.14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., .sup.3H) and carbon-14 (i.e., .sup.14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., .sup.2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
(204) In another aspect provided herein are compounds of Formula (I) selected from a compound of Formula (Ia) and Formula (Ib) for use in the methods described herein: polymorphic crystalline and amorphous forms of the compounds of Formula (I) and of the salts, solvates, hydrates, esters and prodrugs of the compounds of Formula (I) are further intended to be included in the present description.
(205) Compound names provided herein were obtained using ACD Labs Index Name software provided by ACD Labs and/or ChemDraw Ultra software provided by CambridgeSoft®. When the compound name disclosed herein conflicts with the structure depicted, the structure shown will supercede the use of the name to define the compound intended. Nomenclature for substituent radicals defined herein may differ slightly from the chemical name from which they are derived; one skilled in the art will recognize that the definition of the substituent radical is intended to include the radical as found in the chemical name.
(206) As used herein the term “aberrant” refers to a deviation from the norm of, e.g., the average healthy subject or a cell(s) or tissue sample from a healthy subject. The term “aberrant expression,” as used herein, refers to abnormal expression (up-regulated or down-regulated resulting in an excessive or deficient amount thereof) of a gene product (e.g., RNA transcript or protein) by a cell, tissue sample, or subject relative to a corresponding normal, healthy cell, tissue sample or subject. In a specific aspect, the “aberrant expression” refers to an altered level of a gene product (e.g., RNA transcript or protein) in a cell, tissue sample, or subject relative to a corresponding normal, healthy cell, tissue sample or subject. The term “aberrant amount” as used herein refers to an altered level of a gene product (e.g., RNA, protein, polypeptide, or peptide) in a cell, tissue sample, or subject relative to a corresponding normal, healthy cell, tissue sample or subject. In specific aspects, the amount of a gene product (e.g., RNA, protein, polypeptide, or peptide) in a cell, tissue sample, or subject relative to a corresponding cell or tissue sample from a healthy subject or a healthy subject, is considered aberrant if it is 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6-fold or more above or below the amount of the gene product in the corresponding cell or tissue sample from a healthy subject or healthy subject.
(207) The term “intronic REMS” refers to a REMS sequence present in an intron that functions as a 5′ splice site in the presence of a compound described herein. The intronic REMS, when downstream of a first branch point (BP) sequence and a first 3′ splice site (3′ ss) sequence and upstream of a second branch point (BP) sequence and a second 3′ splice site (3′ ss) sequence) (as shown in
(208) As used herein, a “non-endogenous” nucleotide sequence (such as a non-endogenous 5′ splice site, a non-endogenous branch point or a non-endogenous 3′ splice site) is a nucleotide sequence not naturally found to be part of a pre-RNA or a DNA sequence encoding a pre-RNA sequence. In other words, the hand of man is required to synthesize or manipulate the RNA or DNA sequence to introduce the nucleotide sequence.
(209) As used herein, the term “non-endogenous intronic REMS” refers to a REMS sequence not naturally found to be part of an RNA sequence or naturally encoded by a DNA sequence. In other words, the hand of man is required to synthesize or manipulate the RNA or DNA sequence to introduce the intronic REMS or the nucleotide sequence encoding the intronic REMS.
(210) As used herein, the terms “intron-derived exon,” “intronic exon,” “iExon” and “intronic exon” (collectively iExon) refer to an exon that is produced from an intronic RNA sequence when an intronic REMS sequence, a branch point, a 3′ splice site and a splicing modifier compound are present. In particular, when RNA splicing of an RNA transcript comprising two exons and an intron occurs in the presence of a compound described herein, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, and wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an iREMS, a second branch point, and a second 3′ splice site, a resulting iExon comprises the following RNA sequence: the RNA sequence between the first 3′ splice site and the iREMS (corresponding to iExon 1a as shown in
(211) As used herein, the term “pseudoexon” refers to known endogenous intronic sequences naturally present in intron coding DNA that may match those of a branch point, a 3′ splice site and a 5′ splice site, yet is neither active in the splicing process, spliced nor present in the mature mRNA. Some pseudoexons contain an intronic REMS at their 5′ splice site. An intronic REMS-containing pseudoexon is not known to be endogenously recognized by the splicing machinery for producing an iExon but in the presence of a splicing modifier compound as described herein, the splicing machinery produces an iExon. Accordingly, production of an iExon from a pseudoexon is intended to be included within the scope of various aspects of the collective term “iExon.”
(212) As used herein, the term “unannotated exon” refers to endogenous sequences that are naturally present as exons in mature mRNA product according to experimental evidence but are not annotated in NCBI's RefSeq database (https://www.ncbi.nlm.nih.gov/refseq/). Some unannotated exons contain an intronic REMS at the 5′ splice site. A REMS-containing unannotated exon is not known to be endogenously recognized by the splicing machinery for producing an iExon, but in the presence of a splicing modifier compound as described herein, the splicing machinery produces an iExon. Accordingly, production of an iExon from an unannotated exon is intended to be included within the scope of various aspects of the collective term “iExon.”
(213) As used herein, the terms “extended exon” (i.e., eExon) refer to an exon that includes an exon and a portion of an adjacent intronic sequence when an intronic REMS sequence, a branch point, a 3′ splice site and a splicing modifier compound are present in, e.g., the order shown in
(214) As used herein, the term “substantial change” in the context of the amount of one or more RNA transcripts (e.g., rRNA, tRNA, miRNA, siRNA, piRNA, lncRNA, pre-mRNA or mRNA transcripts), an alternative splice variant thereof or an isoform thereof, or one or more proteins thereof, each expressed as the product of one or more of genes, means that the amount of such products changes by a statistically significant amount such as, in a nonlimiting example, a p value less than a value selected from 0.1, 0.01, 0.001, or 0.0001.
(215) As used herein, the terms “subject” and “patient” are used interchangeably to refer to an animal or any living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Non-limiting examples include members of the human, equine, porcine, bovine, rattus, murine, canine and feline species. In some aspects, the subject is a mammal or a warm-blooded vertebrate animal. In certain aspects, the subject is a non-human animal. In specific aspects, the subject is a human.
(216) As used herein, the term “functional protein” refers to a form of a protein that retains a certain biological function or the functions of a full-length protein or protein isoform encoded by a gene.
(217) As used herein, the term “non-functional protein” refers to a form of a protein that does not retain any biological function compared to full length protein or a protein isoform encoded by a gene in the absence of a splicing modifier compound as described herein.
(218) As used herein, in the context of a functional protein produced from an artificial construct, the term “produce substantially less” means that the amount of functional protein produced in the presence of a compound described herein is at least substantially 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% less than the amount of functional protein produced in the absence of the compound.
(219) Methods for Determining Whether Expression of a Gene May be Modulated or Modified by the Compounds
(220) In another aspect, provided herein are methods for determining whether the splicing of the precursor RNA of a gene is likely to be modified by a compound of Formula (I) or a form thereof, comprising searching for the presence of an intronic REMS (i.e., a sequence functioning as a 5′ splice site responsive to the presence of compound) in a gene intronic sequence, wherein the presence of the intronic REMS, 3′ splice site and an intronic branch point in the gene sequence indicates that the splicing of the precursor RNA of the gene is likely to be modified by the compound of Formula (I) or a form thereof, and the absence of the intronic REMS and an intronic 3′ splice site and an intronic branch point in the gene sequence indicates that the splicing of the precursor RNA of the gene is unlikely to be modified by the compound of Formula (I) or a form thereof. In specific aspects, the methods further comprise searching for the presence of the combination of an intronic REMS, an intronic 3′ splice site and an intronic branch point in the gene sequence.
(221) In another aspect, provided herein are methods for determining whether the amount of a product (e.g., an mRNA transcript or protein) of a gene is likely to be modulated by a compound of Formula (I) or a form thereof, comprising searching for the presence of an intronic REMS in the gene sequence, wherein the presence of the combination of an intronic REMS, an intronic 3′ splice site and an intronic branch point in the gene sequence indicates that the amount of a product (e.g., an mRNA transcript or protein) of the gene is likely to be modulated by the compound of Formula (I) or a form thereof, and the absence of the combination of an intronic REMS, an intronic 3′ splice site and an intronic branch point in the gene sequence indicates that the amount of a product (e.g., an mRNA transcript or protein) of the gene is unlikely to be modulated by the compound of Formula (I) or a form thereof. In specific aspects, the methods further comprise searching for the presence of any of an intronic REMS, an intronic 3′ splice site, and an intronic branch point in the gene sequence. In specific aspects, the methods further comprise searching for the presence of the combination of an intronic REMS, a downstream branch point and a downstream 3′ splice site in the gene sequence.
(222) The step of searching for the presence of the minimally required combination of an intronic REMS, a downstream 3′ splice site, and a downstream branch point in the gene sequence described herein can be performed by a computer system comprising a memory storing instructions for searching for the presence of the combination in the gene sequence, or such a search can be performed manually.
(223) In certain aspects, the splicing of a precursor RNA containing an intronic REMS is assessed by contacting a compound described herein with the precursor RNA in cell culture. In some aspects, the splicing of a precursor RNA containing an intronic REMS is assessed by contacting a compound described herein with the precursor RNA in a cell-free extract. In a specific aspect, the compound is one known to modulate the splicing of a precursor RNA containing an intronic REMS. See, e.g., the section below relating to methods for determining whether a compound modulates the expression of certain genes, and the example below for techniques that could be used in these assessments.
(224) Methods for Determining which Compounds Modulate or Modify Expression of Certain Genes
(225) Provided herein are methods for determining whether a compound of Formula (I) or a form thereof modulates the amount of one, two, three or more RNA transcripts (e.g., pre-mRNA or mRNA transcripts or isoforms thereof) of one, two, three or more genes. In some aspects, the gene is any one of the genes described herein.
(226) In one aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript, comprising: (a) contacting a cell(s) with a compound of Formula (I) or a form thereof, and (b) determining the amount of the RNA transcript produced by the cell(s), wherein modulation in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first cell(s) with a compound of Formula (I) or a form thereof, (b) contacting a second cell(s) with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of the RNA transcript produced by the first cell(s) and the second cell(s); and (d) comparing the amount of the RNA transcript produced by the first cell(s) to the amount of the RNA transcript expressed by the second cell(s), wherein modulation in the amount of the RNA transcript produced by the first cell(s) relative to the amount of the RNA transcript produced by the second cell(s) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In certain aspects, the contacting of the cell(s) with the compound occurs in cell culture. In other aspects, the contacting of the cell(s) with the compound occurs in a subject, such as a non-human animal subject.
(227) In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modifies the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof; and (b) determining the amount of the two or more RNA transcript splice variants produced by the cell(s), wherein modulation in the amount of the two or more RNA transcript in the presence of the compound relative to the amount of the two or more RNA transcript splice variants in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modifies the splicing of the RNA transcript.
(228) In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modifies the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof; (b) isolating two or more RNA transcript splice variants from the cell(s) after a certain period of time; and (c) determining the amount of the two or more RNA transcript splice variants produced by the cell(s), wherein modulation in the amount of the two or more RNA transcript in the presence of the compound relative to the amount of the two or more RNA transcript splice variants in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modifies the splicing of the RNA transcript. In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modifies the splicing of an RNA transcript (e.g., an mRNA transcript), comprising (a) culturing a first cell(s) in the presence of a compound of Formula (I) or a form thereof; (b) culturing a second cell(s) in the presence of a negative control (e.g., a vehicle control, such as PBS or DMSO); (c) isolating two or more RNA transcript splice variants produced by the first cell(s) and isolating two or more RNA transcript splice variants produced by the second cell(s); (d) determining the amount of the two or more RNA transcript splice variants produced by the first cell(s) and the second cell(s); and (e) comparing the amount of the two or more RNA transcript splice variants produced by the first cell(s) to the amount of the two or more RNA transcript splice variants produced by the second cell(s), wherein modulation in the amount of the two or more RNA transcript splice variants produced by the first cell(s) relative to the amount of the two or more RNA transcript splice variants produced by the second cell(s) indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript.
(229) In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a cell-free system with a compound of Formula (I) or a form thereof, and (b) determining the amount of the RNA transcript produced by the cell-free system, wherein modulation in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first cell-free system with a compound of Formula (I) or a form thereof, (b) contacting a second cell-free system with a negative control (e.g., a vehicle control, such as PBS or DMSO): and (c) determining the amount of the RNA transcript produced by the first cell-free system and the second cell-free system; and (d) comparing the amount of the RNA transcript produced by the first cell-free system to the amount of the RNA transcript expressed by the second cell-free system, wherein modulation in the amount of the RNA transcript produced by the first cell-free system relative to the amount of the RNA transcript produced by the second cell-free system indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In certain aspects, the cell-free system comprises purely synthetic RNA, synthetic or recombinant (purified) enzymes, and protein factors. In other aspects, the cell-free system comprises RNA transcribed from a synthetic DNA template, synthetic or recombinant (purified) enzymes, and protein factors. In other aspects, the cell-free system comprises purely synthetic RNA and nuclear extract. In other aspects, the cell-free system comprises RNA transcribed from a synthetic DNA template and nuclear extract. In other aspects, the cell-free system comprises purely synthetic RNA and whole cell extract. In other aspects, the cell-free system comprises RNA transcribed from a synthetic DNA template and whole cell extract. In certain aspects, the cell-free system additionally comprises regulatory RNAs (e.g., microRNAs).
(230) In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modifies the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a cell-free system with a compound of Formula (I) or a form thereof; and (b) determining the amount of two or more RNA transcript splice variants produced by the cell-free system, wherein modulation in the amount of the two or more RNA transcript splice variants in the presence of the compound relative to the amount of the two or more RNA transcript splice variants in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modifies the splicing of the RNA transcript. In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modifies the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first cell-free system with a compound of Formula (I) or a form thereof; (b) contacting a second cell-free system with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of two or more RNA transcript splice variants produced by the first cell-free system and the second cell-free system; and (d) comparing the amount of the two or more RNA transcript splice variants produced by the first cell-free system to the amount of the RNA transcript expressed by the second cell-free system, wherein modulation in the amount of the two or more RNA transcript splice variants produced by the first cell-free system relative to the amount of the two or more RNA transcript splice variants produced by the second cell-free system indicates that the compound of Formula (I) or a form thereof modifies the splicing of the RNA transcript. In certain aspects, the cell-free system comprises purely synthetic RNA, synthetic or recombinant (purified) enzymes, and protein factors. In other aspects, the cell-free system comprises RNA transcribed from a synthetic DNA template, synthetic or recombinant (purified) enzymes, and protein factors. In other aspects, the cell-free system comprises purely synthetic RNA and nuclear extract. In other aspects, the cell-free system comprises RNA transcribed from a synthetic DNA template and nuclear extract. In other aspects, the cell-free system comprises purely synthetic RNA and whole cell extract. In other aspects, the cell-free system comprises RNA transcribed from a synthetic DNA template and whole cell extract. In certain aspects, the cell-free system additionally comprises regulatory RNAs (e.g., microRNAs).
(231) In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof, (b) isolating the RNA transcript from the cell(s) after a certain period of time; and (c) determining the amount of the RNA transcript produced by the cell(s), wherein modulation in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising (a) culturing a first cell(s) in the presence of a compound of Formula (I) or a form thereof, (b) culturing a second cell(s) in the presence of a negative control (e.g., a vehicle control, such as PBS or DMSO); (c) isolating the RNA transcript produced by the first cell(s) and isolating the RNA transcript produced by the second cell(s); (d) determining the amount of the RNA transcript produced by the first cell(s) and the second cell(s); and (e) comparing the amount of the RNA transcript produced by the first cell(s) to the amount of the RNA transcript produced by the second cell(s), wherein modulation in the amount of the RNA transcript produced by the first cell(s) relative to the amount of the RNA transcript produced by the second cell(s) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript.
(232) In certain aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject. In some aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject with a disease. In specific aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject with a disease associated with an aberrant amount of an RNA transcript(s) for a particular gene(s). In some specific aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject with a disease associated with an aberrant amount of an isoform(s) of a particular gene(s). In some aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a fibroblast (e.g., GM03813 or PNN 1-46 fibroblasts), an immune cell (e.g., a T cell, B cell, natural killer cell, macrophage), or a muscle cell. In certain aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell.
(233) In certain aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is from a cell line. In some aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cell line derived from a subject with a disease. In certain aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is from a cell line known to have aberrant RNA transcript levels for a particular gene(s). In specific aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is from a cell line derived from a subject with a disease known to have aberrant RNA transcript levels for a particular gene(s). In certain aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell line.
(234) In some specific aspects, the cell(s) contacted or cultured with the compound of Formula (I) or a form thereof is from a cell line derived from a subject with a disease known to have an aberrant amount of an RNA isoform(s) and/or protein isoform(s) of a particular gene(s). Non-limiting examples of cell lines include 3T3, 4T1, 721, 9L, A2780, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1, BEAS-2B, bEnd.3, BHK, BR 293, BT20, BT483, BxPC3, C2C12, C3H-10T1/2, C6/36, C6, Cal-27, CHO, COR-L23, COS, COV-434, CML T1, CMT, CRL7030, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299, H69, HB54, HB55, HCA2, HD-1994, HDF (human dermal fibroblasts), HEK-293, HeLa, Hepa1c1c7, HL-60, HMEC, Hs578T, HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22, KG1, KYO1, LNCap, Ma-Mel, MC-38, MCF-7, MCF-10A, MDA-MB-231, MDA-MB-468, MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69, NIH-3T3, NALM-1, NSO, NW-145, OPCN, OPCT, PNT-1A, PNT-2, Raji, RBL, RenCa, RIN-5F, RMA, Saos-2, Sf21, Sf9, SH-SY5Y, SiHa, SKBR3, SKOV-3, T2, T-47D, T84, THP1, U373, U87, U937, VCaP, Vero, VERY, W138, WM39, WT-49, X63, YAC-1, and YAR cells. In one aspect, the cells are from a patient. In another aspect, the patient cells are GM03813 cells. In another aspect, the patient cells are GM04856, GM04857, GM9197, GM04281, GM04022, GM07492 cells.
(235) In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a tissue sample with a compound of Formula (I) or a form thereof; and (b) determining the amount of the RNA transcript produced by the tissue sample, wherein modulation in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first tissue sample with a compound of Formula (I) or a form thereof, (b) contacting a second tissue sample with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of the RNA transcript produced by the first tissue sample and the second tissue sample; and (d) comparing the amount of the RNA transcript produced by the first tissue sample to the amount of the RNA transcript produced by the second tissue sample, wherein modulation in the amount of the RNA transcript produced by the first tissue sample relative to the amount of the RNA transcript produced by the second tissue sample indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. Any tissue sample containing cells may be used in the accordance with these methods. In certain aspects, the tissue sample is a blood sample, a skin sample, a muscle sample, or a tumor sample. Techniques known to one skilled in the art may be used to obtain a tissue sample from a subject.
(236) In some aspects, a dose-response assay is performed. In one aspect, the dose response assay comprises: (a) contacting a cell(s) with a concentration of a compound of Formula (I) or a form thereof; (b) determining the amount of the RNA transcript produced by the cell(s), wherein modulation in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript; (c) repeating steps (a) and (b), wherein the only experimental variable changed is the concentration of the compound or a form thereof; and (d) comparing the amount of the RNA transcript produced at the different concentrations of the compound or a form thereof. In another aspect, the dose response assay comprises: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof; (b) isolating the RNA transcript from the cell(s) after a certain period; (c) determining the amount of the RNA transcript produced by the cell(s), wherein modulation in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript; (d) repeating steps (a), (b), and (c), wherein the only experimental variable changed is the concentration of the compound or a form thereof; and (e) comparing the amount of the RNA transcript produced at the different concentrations of the compound or a form thereof. In another aspect, the dose-response assay comprises: (a) contacting each well of a microtiter plate containing cells with a different concentration of a compound of Formula (I) or a form thereof: (b) determining the amount of an RNA transcript produced by cells in each well; and (c) assessing the change of the amount of the RNA transcript at the different concentrations of the compound or form thereof.
(237) In one aspect, the dose response assay comprises: (a) contacting a cell(s) with a concentration of a compound of Formula (I) or a form thereof, wherein the cells are within the wells of a cell culture container (e.g., a 96-well plate) at about the same density within each well, and wherein the cells are contacted with different concentrations of compound in different wells; (b) isolating the RNA from said cells in each well; (c) determining the amount of the RNA transcript produced by the cell(s) in each well; and (d) assessing change in the amount of the RNA transcript in the presence of one or more concentrations of compound relative to the amount of the RNA transcript in the presence of a different concentration of the compound or the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO).
(238) In certain aspects, the contacting of the cell(s) with the compound occurs in cell culture. In other aspects, the contacting of the cell(s) with the compound occurs in a subject, such as a non-human animal subject.
(239) In certain aspects described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a compound of Formula (I) or a form thereof, or a negative control for a period of 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72 hours or longer. In other aspects described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a compound of Formula (I) or a form thereof, or a negative control for a period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12 hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24 to 48 hours, 48 to 72 hours.
(240) In certain aspects described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 0.0001 μM, 0.0003 μM, 0.001 μM, 0.003 μM, 0.01 μM, 0.05 μM, 1 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 50 μM, 75 μM, 100 μM, or 150 μM. In other aspects described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 0.0001 μM, 0.0003 μM, 0.0005 μM, 0.001 μM, 0.003 μM, 0.005 μM, 0.01 μM, 0.03 μM, 0.05 μM, 0.1 μM, 0.3 μM, 0.5 μM or 1 μM. In other aspects described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 175 μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 μM, 450 μM, 500 μM, 550 μM, 600 μM, 650 μM, 700 μM, 750 μM, 800 μM, 850 μM, 900 μM, 950 μM or 1 mM. In some aspects described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, or 950 nM. In certain aspects described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is between 0.0001 μM to 0.001 μM, 0.0001 μM to 0.01 μM, 0.0003 μM to 0.001 μM, 0.0003 μM to 0.01 μM, 0.001 μM to 0.01 μM, 0.003 μM to 0.01 μM, 0.01 μM to 0.1 μM, 0.1 μM to 1 μM, 1 μM to 50 μM, 50 μM to 100 μM, 100 μM to 500 μM, 500 μM to 1 nM, 1 nM to 10 nM, 10 nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM.
(241) In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a subject (in certain aspects, a non-human animal); and (b) determining the amount of the RNA transcript in a sample obtained from the subject, wherein modulation in the amount of the RNA transcript measured in the sample from the subject administered the compound or form thereof relative to the amount of the RNA transcript in a sample from the subject prior to administration of the compound or form thereof or a sample from a different subject from the same species not administered the compound or form thereof indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a first subject (in certain aspects, a non-human animal); (b) administering an inactive control (e.g., a pharmaceutical carrier) to a second subject (in certain aspects, a non-human animal) of the same species as the first subject; and (c) determining the amount of the RNA transcript in a first tissue sample from the first subject and the amount of the RNA transcript in the second tissue sample from the second subject; and (d) comparing the amount of the RNA transcript in the first tissue sample to the amount of the RNA transcript in the second tissue sample, wherein modulation in the amount of the RNA transcript in the first tissue sample relative to the amount of the RNA transcript in the second tissue sample indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In certain aspects, a compound of Formula (I) or form thereof is administered to a subject at a dose of about 0.001 mg/kg/day to about 500 mg/kg/day. In some aspects, a single dose of a compound of Formula (I) or a form thereof is administered to a subject in accordance with the methods described herein. In other aspects, 2, 3, 4, 5 or more doses of a compound of Formula (I) is administered to a subject in accordance with the methods described herein. In specific aspects, the compound of Formula (I) or a form thereof is administered in a subject in a pharmaceutically acceptable carrier, excipient or diluent.
(242) In another aspect, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modifies the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a subject (in certain aspects, a non-human animal); and (b) determining the amount of two or more RNA transcript splice variants in a sample obtained from the subject, wherein modulation in the amount of the two or more RNA transcript splice variants measured in the sample from the subject administered the compound or form thereof relative to the amount of the two or more RNA transcript splice variants in a sample from the subject prior to administration of the compound or form thereof or a sample from a different subject from the same species not administered the compound or form thereof indicates that the compound of Formula (I) or a form thereof modifies the splicing of the RNA transcript. In another aspects, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modifies the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a first subject (in certain aspects, a non-human animal); (b) administering a negative control (e.g., a pharmaceutical carrier) to a second subject (in certain aspects, a non-human animal) of the same species as the first subject; (c) determining the amount of two or more RNA transcript splice variants in a first tissue sample from the first subject and the amount of two or more RNA transcript splice variants in the second tissue sample from the second subject; and (d) comparing the amount of the two or more RNA transcript splice variants in the first tissue sample to the amount of the two or more RNA transcript splice variants in the second tissue sample, wherein modulation in the amount of the two or more RNA transcript splice variants in the first tissue sample relative to the amount of the two or more RNA transcript splice variants in the second tissue sample indicates that the compound of Formula (I) or a form thereof modifies the splicing of the RNA transcript. In certain aspects, a compound of Formula (I) or form thereof is administered to a subject at a dose of about 0.001 mg/kg/day to about 500 mg/kg/day. In some aspects, a single dose of a compound of Formula (I) or a form thereof is administered to a subject in accordance with the methods described herein. In other aspects, 2, 3, 4, 5 or more doses of a compound of Formula (I) is administered to a subject in accordance with the methods described herein. In specific aspects, the compound of Formula (I) or a form thereof is administered in a subject in a pharmaceutically acceptable carrier, excipient or diluent.
(243) In some aspects, the compound of Formula (I) or a form thereof that is contacted or cultured with a cell(s) or a tissue sample, or administered to a subject is a compound described herein.
(244) Techniques known to one skilled in the art may be used to determine the amount of an RNA transcript(s). In some aspects, the amount of one, two, three or more RNA transcripts is measured using deep sequencing, such as ILLUMINA® RNASeq, ILLUMINA® next generation sequencing (NGS), ION TORRENT® RNA next generation sequencing, 454™ pyrosequencing, or Sequencing by Oligo Ligation Detection (SOLID™), Single Molecule, Real-Time (SMRT) sequencing, Nanopore sequencing. In other aspects, the amount of multiple RNA transcripts is measured using an exon array, such as the GENECHIP® human exon array. In certain aspects, the amount of one, two, three or more RNA transcripts is determined by RT-PCR. In other aspects, the amount of one, two, three or more RNA transcripts is measured by RT-qPCR or digital color-coded barcode technology. Techniques for conducting these assays are known to one skilled in the art.
(245) In some aspects, analysis is performed on data derived from the assay to measure the magnitude of splicing to determine the amount of exons spliced into an mRNA transcript that is produced in the presence of the compound relative to the amount in the absence of the compound or presence of a negative control. In a preferred aspect, the method utilized is calculation of change in Percent Spliced In (ΔPSI). The method utilizes read data from RNAseq (or any other method that can distinguish mRNA splice isoforms) to calculate the ratio (percentage) between reads that either demonstrate inclusion (junctions between the upstream exon and the exon of interest) or exclusion (junction between the upstream and downstream exons, excluding the exon of interest), to demonstrate whether the presence of the compound affects the amount of exon inclusion relative to the amount of inclusion in the absence of the compound or the presence of a negative control.
(246) The ΔPSI value is derived from the formula:
ΔPSI (%)=C−U×100
(247) Where “U” represents the value for probability of iExon inclusion (a+b)/2/[(a+b)/2+c] in the absence of the compound; and, where “C” represents the value for probability of iExon inclusion (a+b)/2/[(a+b)/2+c] in the presence of the compound. The values for “a” and “b” represent the number of reads supporting inclusion of an iExon in an RNA transcript. In other words, the “a” value is derived from the amount of reads for a first intronic nucleotide sequence comprising, in 5′ to 3′ order: a first exon 5′ splice site operably linked and upstream from a first intronic nucleotide sequence comprising a first branch point further operably linked and upstream from a first intronic 3′ splice site (upstream of the nascent iExon). The “b” value is derived from the amount of reads for a second intronic nucleotide sequence comprising, in 5′ to 3′ order: a REMS sequence operably linked and upstream from a second intronic nucleotide sequence comprising a second branch point further operably linked and upstream from a second intronic 3′ splice site of a second exon. The value for “c” represents the number of reads supporting exclusion of an iExon. Accordingly, when a compound enables the splicing machinery to recognize a nascent iExon, the value for “C” in the presence of the splicing modulates compound will differ from the value for “U” in the absence of the compound. The statistically significant value for the likelihood of iExon inclusion may be obtained according to statistical analysis methods or other probability analysis methods known to those of ordinary skill in the art.
(248) In some aspects, a statistical analysis or other probability analysis is performed on data from the assay utilized to measure an RNA transcript. In certain aspects, for example, a Fisher's Exact Test statistical analysis is performed by comparing the total number of read for the inclusion and exclusion of an iExon (or region) based on data from one or more assays used to measure whether the amount of an RNA transcript is modulated in the presence of the compound relative to the amount in the absence of the compound or presence of a negative control. In specific aspects, the statistical analysis results in a confidence value for those modulated RNA transcripts of 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001%. In some specific aspects, the confidence value is a p value for those modulated RNA transcripts of 10%, 5%, 4%,3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001%. In certain specific aspects, an exact test, student t-test or p value for those modulated RNA transcripts is 10, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% and 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.01%, 0.001% or 0.0001%, respectively.
(249) In certain aspects, a further analysis is performed to determine how the compound of Formula (I) or a form thereof is changing the amount of an RNA transcript(s). In specific aspects, a further analysis is performed to determine if modulation in the amount of an RNA transcript(s) in the presence of a compound of Formula (I) or a form thereof relative the amount of the RNA transcript(s) in the absence of the compound or a form thereof, or the presence of a negative control is due to changes in transcription, splicing, and/or stability of the RNA transcript(s). Techniques known to one skilled in the art may be used to determine whether a compound of Formula (I) or a form thereof changes, e.g., the transcription, splicing and/or stability of an RNA transcript(s).
(250) In certain aspects, the stability of one or more RNA transcripts is determined by serial analysis of gene expression (SAGE), differential display analysis (DD), RNA arbitrary primer (RAP)-PCR, restriction endonuclease-lytic analysis of differentially expressed sequences (READS), amplified restriction fragment-length polymorphism (ALFP), total gene expression analysis (TOGA), RT-PCR, RT-RPA (recombinase polymerase amplification), RT-qPCR, RNA-Seq, digital color-coded barcode technology, high-density cDNA filter hybridization analysis (HDFCA), suppression subtractive hybridization (SSH), differential screening (DS), cDNA arrays, oligonucleotide chips, or tissue microarrays. In other aspects, the stability of one or more RNA transcripts is determined by Northern blot, RNase protection, or slot blot.
(251) In some aspects, the transcription in a cell(s) or tissue sample is inhibited before (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours before) or after (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours after) the cell or the tissue sample is contacted or cultured with an inhibitor of transcription, such as α-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D. In other aspects, the transcription in a cell(s) or tissue sample is inhibited with an inhibitor of transcription, such as α-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D, while the cell(s) or tissue sample is contacted or cultured with a compound of Formula (I) or a form thereof.
(252) In certain aspects, the level of transcription of one or more RNA transcripts is determined by nuclear run-on assay or an in vitro transcription initiation and elongation assay. In some aspects, the detection of transcription is based on measuring radioactivity or fluorescence. In some aspects, a PCR-based amplification step is used.
(253) In specific aspects, the amount of alternatively spliced forms of the RNA transcripts of a particular gene are measured to see if there is modulation in the amount of one, two or more alternatively spliced forms of the RNA transcripts of the gene. In some aspects, the amount of an isoform(s) encoded by a particular gene is measured to see if there is modulation in the amount of the isoform(s). In certain aspects, the levels of spliced forms of RNA are quantified by RT-PCR, RT-qPCR, RNA-Seq, digital color-coded barcode technology, or Northern blot. In other aspects, sequence-specific techniques may be used to detect the levels of an individual spliceoform. In certain aspects, splicing is measured in vitro using nuclear extracts. In some aspects, detection is based on measuring radioactivity or fluorescence. Techniques known to one skilled in the art may be used to measure modulation in the amount of alternatively spliced forms of an RNA transcript of a gene and modulation in the amount of an isoform encoded by a gene.
(254) Pharmaceutical Compositions and Modes of Administration
(255) When administered to a patient, a compound of Formula (I) or a form thereof is preferably administered as a component of a composition that optionally comprises a pharmaceutically acceptable carrier, excipient or diluent. The composition can be administered orally, or by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa) and may be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, and can be used to administer the compound.
(256) Methods of administration include, but are not limited to, parenteral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intraocular, intratumoral, intracerebral, intravaginal, transdermal, ocularly, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the practitioner. In most instances, administration will result in the release of a compound into the bloodstream, tissue or cell(s). In a specific aspect, a compound is administered orally.
(257) The amount of a compound of Formula (I) or a form thereof that will be effective in the treatment of a disease resulting from an aberrant amount of mRNA transcripts depends, e.g., on the route of administration, the disease being treated, the general health of the subject, ethnicity, age, weight, and gender of the subject, diet, time, and the severity of disease progress, and should be decided according to the judgment of the practitioner and each patient's or subject's circumstances.
(258) In specific aspects, an “effective amount” in the context of the administration of a compound of Formula (I) or a form thereof, or composition or medicament thereof refers to an amount of a compound of Formula (I) or a form thereof to a patient which has a therapeutic effect and/or beneficial effect. In certain specific aspects, an “effective amount” in the context of the administration of a compound of Formula (I) or a form thereof, or composition or medicament thereof to a patient results in one, two or more of the following effects: (i) reduces or ameliorates the severity of a disease; (ii) delays onset of a disease; (iii) inhibits the progression of a disease; (iv) reduces hospitalization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the quality of life of a subject; (viii) reduces the number of symptoms associated with a disease; (ix) reduces or ameliorates the severity of a symptom(s) associated with a disease; (x) reduces the duration of a symptom associated with a disease associated; (xi) prevents the recurrence of a symptom associated with a disease; (xii) inhibits the development or onset of a symptom of a disease; and/or (xiii) inhibits of the progression of a symptom associated with a disease. In certain aspects, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to restore the amount of a RNA transcript of a gene to the amount of the RNA transcript detectable in healthy patients or cells from healthy patients. In other aspects, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to restore the amount an RNA isoform and/or protein isoform of gene to the amount of the RNA isoform and/or protein isoform detectable in healthy patients or cells from healthy patients.
(259) In certain aspects, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to decrease the aberrant amount of an RNA transcript of a gene which associated with a disease. In certain aspects, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to decrease the amount of the aberrant expression of an isoform of a gene. In some aspects, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to result in a substantial change in the amount of an RNA transcript (e.g., mRNA transcript), alternative splice variant or isoform.
(260) In certain aspects, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to increase or decrease the amount of an RNA transcript (e.g., an mRNA transcript) of gene which is beneficial for the prevention and/or treatment of a disease. In certain aspects, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to increase or decrease the amount of an alternative splice variant of an RNA transcript of gene which is beneficial for the prevention and/or treatment of a disease. In certain aspects, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to increase or decrease the amount of an isoform of gene which is beneficial for the prevention and/or treatment of a disease. Non-limiting examples of effective amounts of a compound of Formula (I) or a form thereof are described herein.
(261) For example, the effective amount may be the amount required to prevent and/or treat a disease associated with the aberrant amount of an mRNA transcript of gene in a human subject.
(262) In general, the effective amount will be in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day for a patient having a weight in a range of between about 1 kg to about 200 kg. The typical adult subject is expected to have a median weight in a range of between about 70 and about 100 kg.
(263) Within the scope of the present description, the “effective amount” of a compound of Formula (I) or a form thereof for use in the manufacture of a medicament, the preparation of a pharmaceutical kit or in a method for preventing and/or treating a disease in a human subject in need thereof, is intended to include an amount in a range of from about 0.001 mg to about 35,000 mg.
(264) The compositions described herein are formulated for administration to the subject via any drug delivery route known in the art. Non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.
(265) Aspects described herein include the use of a compound of Formula (I) or a form thereof in a pharmaceutical composition. In a specific aspect, described herein is the use of a compound of Formula (I) or a form thereof in a pharmaceutical composition for preventing and/or treating a disease in a human subject in need thereof comprising administering an effective amount of a compound of Formula (I) or a form thereof in admixture with a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the human subject is a patient with a disease associated with the aberrant amount of an mRNA transcript(s).
(266) A compound of Formula (I) or a form thereof may optionally be in the form of a composition comprising the compound or a form thereof and an optional carrier, excipient or diluent. Other aspects provided herein include pharmaceutical compositions comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent. In a specific aspect, the pharmaceutical compositions are suitable for veterinary and/or human administration. The pharmaceutical compositions provided herein can be in any form that allows for the composition to be administered to a subject.
(267) In a specific aspect and in this context, the term “pharmaceutically acceptable carrier, excipient or diluent” means a carrier, excipient or diluent approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a specific carrier for intravenously administered pharmaceutical compositions. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
(268) Typical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient and the specific active ingredients in the dosage form. Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising one or more compounds of Formula (I) or a form thereof as described herein. The compositions and single unit dosage forms can take the form of solutions or syrups (optionally with a flavoring agent), suspensions (optionally with a flavoring agent), emulsions, tablets (e.g., chewable tablets), pills, capsules, granules, powder (optionally for reconstitution), taste-masked or sustained-release formulations and the like.
(269) Pharmaceutical compositions provided herein that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets, caplets, capsules, granules, powder, and liquids. Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art.
(270) Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
(271) Methods of Modulating the Amount of RNA Transcripts Encoded by Certain Genes
(272) In one aspect, described herein are methods for modifying RNA splicing in order to modulate the amount of a product of a gene, wherein a precursor RNA transcript transcribed from the gene contains an intronic REMS, and the methods utilize a compound described herein. In certain aspects, the gene is any one of the genes described herein. In certain aspects, the gene contains a nucleotide sequence encoding a non-endogenous intronic REMS. In one aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene described herein, the method comprising contacting a cell with a compound of Formula (I) or a form thereof.
(273) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a product of a gene (such as an RNA transcript or a protein), wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding a first exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding a second exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first 5′ splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, a nucleotide sequence encoding an iREMS, a nucleotide sequence encoding a second branch point and a nucleotide sequence encoding a second 3′ splice site, wherein the nucleotide sequence encoding the iREMS comprises a DNA sequence GAgtrngn, and wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting a cell with a compound described herein (for example, a compound of Formula (I) or a form thereof).
(274) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a product of a gene (such as an RNA transcript or protein), wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding a first exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding a second exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence of the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding an iREMS, a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site, wherein the nucleotide sequence encoding the iREMS comprises a DNA sequence GAgtrngn, and wherein r is adenine or guanine and n is any nucleotide, the method comprising contacting a cell with a compound described herein (for example, a compound of Formula (I) or a form thereof).
(275) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a product of a gene (such as an RNA transcript or protein), wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence encodes exonic and intronic elements illustrated in
(276) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a product of a gene (such as an RNA transcript or protein), wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence encodes exonic and intronic elements illustrated in
(277) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a product of a gene (such as an RNA transcript or protein), wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence encodes exonic and intronic elements illustrated in
(278) In a specific aspect, the gene is a gene described in a table in this disclosure.
(279) In another aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene described herein, wherein the precursor transcript transcribed from the gene comprises an intronic REMS, the method comprising contacting a cell with a compound of Formula (I) or a form thereof. In a specific aspect, the precursor transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(280) In another aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene described herein, wherein the precursor transcript transcribed from the gene comprises an intronic REMS, the method comprising contacting a cell with a compound of Formula (I) or a form thereof. In a specific aspect, the precursor transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(281) In another aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene described herein, comprising contacting a cell with a compound of Formula (I) or a form thereof. See the example section for additional information regarding the genes described herein. In certain aspects, the cell is contacted with the compound of Formula (I) or a form thereof in a cell culture. In other aspects, the cell is contacted with the compound of Formula (I) or a form thereof in a subject (e.g., a non-human animal subject or a human subject).
(282) In one aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon from a pre-mRNA transcript, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide.
(283) In one aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon, the method comprising contacting a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide.
(284) In another aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon, the method comprising contacting a cell or cell lysate containing a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide. In some aspects, the pre-mRNA transcript is encoded by a gene disclosed herein (e.g., in a table herein).
(285) In a particular aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon, the method comprising contacting a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from ABCB8, ABCC3, ADAM17, ADCY3, AGPAT4, ANKRA2, ANXA11, APIP, APPL2, ARHGAP1, ARL15, ASAP1, ASPH, ATAD2B, ATXN1, BECN1, BHMT2, BICD1, BTN3A1, C11orf30, C11orf73, C12orf4, C14orf132, C8orf44, C8orf44-SGK3, C8orf88, CASC3, CASP7, CCDC122, CDH13, CECR7, CENPI, CEP112, CEP192, CHEK1, CMAHP, CNRIP1, COPS7B, CPSF4, CRISPLD2, CRYBG3, CSNK1E, CSNK1G1, DCAF17, DCUN1D4, DDX42, DENND1A, DENND5A, DGKA, DHFR, DIAPH3, DNAJC13, DNMBP, DOCK1, DYRK1A, EIF2B3, ENAH, ENOX1, EP300, ERC1, ERLIN2, ERRFI1, EVC, FAF1, FAIM, FAM126A, FAM13A, FAM162A, FAM174A, FBN2, FER, FHOD3, FOCAD, GALC, GCFC2, GGACT, GLCE, GOLGA4, GOLGB1, GPSM2, GULP1, GXYLT1, HDX, HLTF, HMGA2, HNMT, HSD17B12, HSD17B4, HTT, IFT57, IVD, KDM6A, KIAA1524, KIAA1715, LETM2, LOC400927, LRRC42, LUC7L3, LYRM1, MB21D2, MCM10, MED13L, MEDAG, MEMO1, MFN2, MMS19, MRPL45, MRPS28, MTERF3, MYCBP2, MYLK, MYOF, NGF, NREP, NSUN4, NT5C2, OSMR, OXCT1, PAPD4, PCM1, PDE7A, PDS5B, PDXDC1, PIGN, PIK3CD, PIK3R1, PIKFYVE, PITPNB, PLEKHA1, PLSCR1, PMS1, POMT2, PPARG, PPIP5K2, PPP1R26, PRPF31, PRSS23, PSMA4, PXK, RAF1, RAPGEF1, RARS2, RBKS, RERE, RFWD2, RPA1, RPS10, SAMD4A, SAR1A, SCO1, SEC24A, SENP6, SERGEF, SGK3, SLC12A2, SLC25A17, SLC44A2, SMYD3, SNAP23, SNHG16, SNX7, SOS2, SPATA5, SPIDR, SPRYD7, SRGAP1, SRRM1, STAT1, STXBP6, SUPT20H, TAF2, TASP1, TBC1D15, TCF12, TCF4, TIAM1, TJP2, TMC3, TMEM214, TNRC6A, TNS3, TOE1, TRAF3, TSPAN2, TTC7B, TYW5, UBAP2L, URGCP, VAV2, WDR27, WDR37, WDR91, WNK1, XRN2, ZCCHC8, ZFP82, ZNF138, ZNF232 and ZNF37BP.
(286) In another particular aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon, the method comprising contacting a cell or cell lysate containing a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from ABCB8, ABCC3, ADAM17, ADCY3, AGPAT4, ANKRA2, ANXA11, APIP, APPL2, ARHGAP1, ARL15, ASAP1, ASPH, ATAD2B, ATXN1, BECN1, BHMT2, BICD1, BTN3A1, C11orf30, C11orf73, C12orf4, C14orf132, C8orf44, C8orf44-SGK3, C8orf88, CASC3, CASP7, CCDC122, CDH13, CECR7, CENPI, CEP112, CEP192, CHEK1, CMAHP, CNRIP1, COPS7B, CPSF4, CRISPLD2, CRYBG3, CSNK1E, CSNK1G1, DCAF17, DCUN1D4, DDX42, DENND1A, DENND5A, DGKA, DHFR, DIAPH3, DNAJC13, DNMBP, DOCK1, DYRK1A, EIF2B3, ENAH, ENOX1, EP300, ERC1, ERLIN2, ERRFI1, EVC, FAF1, FAIM, FAM126A, FAM13A, FAM162A, FAM174A, FBN2, FER, FHOD3, FOCAD, GALC, GCFC2, GGACT, GLCE, GOLGA4, GOLGB1, GPSM2, GULP1, GXYLT1, HDX, HLTF, HMGA2, HNMT, HSD17B12, HSD17B4, HTT, IFT57, IVD, KDM6A, KIAA1524, KIAA1715, LETM2, LOC400927, LRRC42, LUC7L3, LYRM1, MB21D2, MCM10, MED13L, MEDAG, MEMO1, MFN2, MMS19, MRPL45, MRPS28, MTERF3, MYCBP2, MYLK, MYOF, NGF, NREP, NSUN4, NT5C2, OSMR, OXCT1, PAPD4, PCM1, PDE7A, PDS5B, PDXDC1, PIGN, PIK3CD, PIK3R1, PIKFYVE, PITPNB, PLEKHA1, PLSCR1, PMS1, POMT2, PPARG, PPIP5K2, PPP1R26, PRPF31, PRSS23, PSMA4, PXK, RAF1, RAPGEF1, RARS2, RBKS, RERE, RFWD2, RPA1, RPS10, SAMD4A, SAR1A, SCO1, SEC24A, SENP6, SERGEF, SGK3, SLC12A2, SLC25A17, SLC44A2, SMYD3, SNAP23, SNHG16, SNX7, SOS2, SPATA5, SPIDR, SPRYD7, SRGAP1, SRRM1, STAT1, STXBP6, SUPT20H, TAF2, TASP1, TBC1D15, TCF12, TCF4, TIAM1, TJP2, TMC3, TMEM214, TNRC6A, TNS3, TOE1, TRAF3, TSPAN2, TTC7B, TYW5, UBAP2L, URGCP, VAV2, WDR27, WDR37, WDR91, WNK1, XRN2, ZCCHC8, ZFP82, ZNF138, ZNF232 and ZNF37BP.
(287) In another particular aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon, the method comprising contacting a cell or cell lysate containing a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM12, ADAM15, ADAM17, ADAM23, ADAM33, ADAMTS1, ADAMTS19, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP8L, AKAP9, AKNA, AKT1, ALCAM, ALDH4A1, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD13C, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APLP2, APOA2, APP, APPL2, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGAP5, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARL5B, ARMCX3, ARMCX6, ARSJ, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF6, ATF7IP, ATG5, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, AXIN1, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3, BIN3-IT1, BIRC3, BIRC6, BNC1, BNC2, BRCA1, BRCA2, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1QTNF9B-AS1, C1orf27, C1orf86, C10orf54, C11orf30, C11orf70, C11orf73, C11orf76, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C2orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CACNB4, CADM1, CADM2, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCNL2, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDH18, CDK11B, CDK16, CDKAL1, CDKN1C, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP162, CEP170, CEP192, CEP57, CEP68, CFH, CFLAR, CHD8, CHEK1, CHRM2, CIITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, CMSS1, CNOT7, CNRIP1, CNTN1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRX, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CTRC, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAAM1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND4A, DENND5A, DEPTOR, DET1, DFNB59, DGCR2, DGK1, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DLGAP4, DMD, DMXL1, DNAH8, DNAH11, DNAJA4, DNAJC13, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEFIA1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELMO2, ELN, ELP4, EMX2OS, ENAH, ENG, ENOX1, ENPP1, ENPP2, ENSA, EP300, EPN1, EPT1, ERC1, ERC2, ERCC1, ERCC8, ERGIC3, ERLIN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXOC3, EXOC6B, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM195B, FAM198B, FAM20A, FAM208B, FAM219A, FAM219B, FAM3C, FAM46B, FAM49B, FAM65A, FAM65B, FAM69B, FAP, FARP1, FBLN2, FBN2, FBXL16, FBXL6, FBXO9, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD4, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GBP1, GCFC2, GLCE, GCNT1, GDF6, GGACT, GGCT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNG12, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GTSF1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HMGXB4, HOOK3, HOXB3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSD17B4, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IKBKAP, IL16, IL6ST, INA, INHBA, INO80, IPP4B, INPP5K, INSIG1, INTU, INVS, IQCE, IQCG, ITCH, ITGA11, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIDINS220, KIF14, KIF2A, KIF21A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LARP7, LATS2, LDLR, LEMD3, LETM2, LGALS3, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, LINC00578, LINC00607, LINC00657, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LINCR-0002, LINGO2, LMAN2L, LMNA, LMO7, LMOD1, LOC400927, LONP1, LOX, LPHN1, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC1, LRRC32, LRRC39, LRRC42, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MACROD2, MADD, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MANEA, MAP4K4, MAPK10, MAPK13, MARCH7, MARCH8, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MDN1, MEAF6, MECP2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MORF4L1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL39, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR3, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYB, MYCBP2, MYLK, MYO1D, MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NEDD4, NELFA, NEO1, NEURL1B, NF2, NFASC, NFE2L1, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLGN1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL3, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PAX6, PBLD, PBX3, PCBP2, PCBP4, PCCB, PCDH10, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE3A, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PDXDC2P, PEAR1, PELI1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPFIBP1, PPHLN1, PPIP5K1, PPIP5K2, PPM1E, PPPIR12A, PPPR26, PPP3CA, PPP6R1, PPP6R2, PRKACB, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTCH1, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB23, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAP1A, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASIP1, RASSF8, RBBP8, RBCK1, RCOR3, RBFOX2, RBKS, RBM10, RCC1, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGL1, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF130, RNF144A, RNF213, RNF38, RNFT1, ROR1, ROR2, RPA1, RPF2, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A1, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SF3B3, SGIP1, SGK3, SGMS1, SGOL2, SGPL1, SH2B3, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SKP1, SLC12A2, SLC24A3, SLC25A16, SLC25A17, SLC34A3, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMN2, SMOX, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SNX24, SNX7, SOCS2, SOCS6, SOGA2, SON, SORBS2, SORCS1, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPINK5, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRGAP1, SRRM1, SRSF3, SSBP1, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRAD8, STRIP1, STRN3, STRN4, STS, STX16, STXBP4, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBCA, TBL1XR1, TBL2, TCF12, TCF4, TCF7L2, TEKT4P2, TENC1, TENM2, TEP1, TET1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFB1, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJAP1, TJP2, TLE3, TLK1, TMC3, TMEM67, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TMX3, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNRC6A, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP531NP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNL4B, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2D3, UBE2G2, UBE2L3, UBE2V1, UBN2, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC3B, UNC5B, URGCP, URGCP-MRPS24, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VDAC2, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR90, WDR91, WHSC2, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XDH, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMIZ2, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF208, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF280D, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF426, ZNF431, ZNF583, ZNF618, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF730, ZNF74, ZNF764, ZNF777, ZNF778, ZNF780A, ZNF7804A, ZNF79, ZNF827, ZNF836, ZNF837, ZNF839, ZNF91 and ZSCAN25.
(288) In another particular aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon, the method comprising contacting a cell or cell lysate containing a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from APOA2, ASAP1, BRCA1, BRCA2, CDKN1C, CRX, CTRC, DENND5A, DIAPH3, DMD, DNAH11, EIF2B3, GALC, HPS1, HTT, IKBKAP, KIAA1524, LMNA, MECP2, PAPD4, PAX6, PCCB, PITPNB, PTCH1, SLC34A3, SMN2, SPINK5, SREK1, TMEM67, VWF, XDH and XRN2.
(289) In another particular aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon, the method comprising contacting a cell or cell lysate containing a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM15, ADAM17, ADAM23, ADAM33, ADAMTS1, ADAMTS19, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP8L, AKAP9, AKNA, ALCAM, ALDH4A, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD13C, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APOA2, APP, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGAP5, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARL5B, ARMCX3, ARSJ, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF6, ATF7IP, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3, BIN3-IT1, BIRC3, BIRC6, BNC1, BNC2, BRCA1, BRCA2, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1QTNF9B-AS1, C1orf27, C1orf86, C10orf54, C11orf30, C11orf70, C11orf73, C11orf76, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C2orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CACNB4, CADM1, CADM2, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCNL2, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDH18, CDK11B, CDK16, CDKAL1, CDKN1C, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP162, CEP170, CEP192, CEP68, CFH, CFLAR, CHD8, CHEK1, CHRM2, CIITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, CMSS1, CNOT7, CNRIP1, CNTN1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRX, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CTRC, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAAM1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND4A, DENND5A, DEPTOR, DET1, DFNB59, DGCR2, DGK1, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DMD, DMXL1, DNAH8, DNAH11, DNAJA4, DNAJC3, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEFIA1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELMO2, ELN, ELP4, EMX2OS, ENAH, ENG, ENOX1, ENPP1, ENPP2, ENSA, EP300, EPT1, ERC1, ERC2, ERCC1, ERCC8, ERLN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXOC3, EXOC6B, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM195B, FAM198B, FAM20A, FAM208B, FAM219A, FAM219B, FAM3C, FAM46B, FAM49B, FAM65A, FAM65B, FAM69B, FAP, FARP1, FBLN2, FBN2, FBXL16, FBXL6, FBXO9, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD4, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GBP1, GCFC2, GLCE, GCNT1, GDF6, GGACT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNG12, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GTSF1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HMGXB4, HOOK3, HOXB3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IKBKAP, IL16, IL6ST, INA, INHBA, INO80, IPP4B, INPP5K, INSIG1, INTU, INVS, IQCE, IQCG, ITCH, ITGA11, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIDINS220, KIF14, KIF2A, KIF21A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LATS2, LDLR, LEMD3, LETM2, LGALS3, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, LINC00578, LINC00607, LINC00657, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LINCR-0002, LINGO2, LMAN2L, LMNA, LMO7, LMOD1, LOC400927, LONP1, LOX, LPHN1, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC1, LRRC32, LRRC39, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MACROD2, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MANEA, MAP4K4, MAPK10, MAPK13, MARCH7, MARCH8, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MDN1, MEAF6, MECP2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MORF4L1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR3, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYB, MYCBP2, MYLK, MYO1D, MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NEDD4, NELFA, NEO1, NEURL1B, NF2, NFASC, NFE2L, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLGN1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL3, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PAX6, PBLD, PBX3, PCBP2, PCCB, PCDH10, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE3A, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PDXDC2P, PEAR1, PELI1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPFIBP1, PPIP5K1, PPIP5K2, PPM1E, PPP1R12A, PPPR26, PPP3CA, PPP6R1, PPP6R2, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTCH1, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASIP1, RASSF8, RBBP8, RBCK1, RCOR3, RBFOX2, RBKS, RBM10, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGL1, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF130, RNF144A, RNF213, RNF38, RNFT1, ROR1, ROR2, RPA1, RPF2, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SF3B3, SGIP1, SGK3, SGMS1, SGOL2, SGPL1, SH2B3, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SKP1, SLC12A2, SLC24A3, SLC25A16, SLC25A17, SLC34A3, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMOX, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SNX24, SNX7, SOCS2, SOCS6, SOGA2, SON, SORBS2, SORCS1, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPINK5, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SRGAP1, SRRM1, SRSF3, SSBP1, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRAD8, STRIP1, STRN4, STS, STX16, STXBP4, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBCA, TBL1XR1, TBL2, TCF12, TCF4, TCF7L2, TEKT4P2, TENC1, TENM2, TEP1, TET1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFB1, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJAP1, TJP2, TLE3, TLK1, TMC3, TMEM67, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TMX3, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF4, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNL4B, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2D3, UBE2G2, UBE2L3, UBE2V1, UBN2, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC13B, UNC5B, URGCP, URGCP-MRPS24, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VDAC2, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR90, WDR91, WHSC2, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XDH, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMIZ2, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF208, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF280D, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF426, ZNF431, ZNF583, ZNF618, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF730, ZNF74, ZNF764, ZNF777, ZNF778, ZNF780A, ZNF7804A, ZNF79, ZNF827, ZNF836, ZNF837, ZNF839, ZNF91 and ZSCAN25.
(290) In another particular aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon, the method comprising contacting a cell or cell lysate containing a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is not SMN2.
(291) In another particular aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon, the method comprising contacting a cell or cell lysate containing a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is not selected from ABHD10, ADAM12, AKT1, ANXA11, APLP2, APPL2, ARMCX6, ATG5, AXIN1, BAIAP2, CCNB1IP1, CCT7, CEP57, CSF1, DLGAP4, EPN1, ERGIC3, FOXM1, GGCT, GRAMD3, HSD17B4, LARP7, LRRC42, MADD, MAN1B1, MRPL39, PCBP4, PPHLN1, PRKACB, RAB23, RAP1A, RCC1, SREK1, STRN3 and TNRC6A.
(292) In another particular aspect, provided herein is a method for modifying RNA splicing in order to produce a mature mRNA transcript having an iExon, the method comprising contacting a cell or cell lysate containing a pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a second branch point, and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is not selected from ABHD10, ADAM12, AKT1, ANXA11, APLP2, APPL2, ARMCX6, ATG5, AXIN1, BAIAP2, CCNB1IP1, CCT7, CEP57, CSF1, DLGAP4, EPN1, ERGIC3, FOXM1, GGCT, GRAMD3, HSD17B4, LARP7, LRRC42, MADD, MAN1B1, MRPL39, PCBP4, PPHLN1, PRKACB, RAB23, RAP1A, RCC1, SMN2, SREK1, STRN3 and TNRC6A.
(293) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide.
(294) In one aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide.
(295) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting a cell or cell lysate containing the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide. In some aspects, the intron further comprises in 5′ to 3′ order: a 5′ splice site, a branch point, and a 3′ splice site upstream of the iREMS. In some aspects, the pre-mRNA transcript is encoded by a gene disclosed herein (e.g., in a table herein).
(296) In a particular aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from ABCA10, ABCB8, ABCC3, ACTA2, ADAL, ADAMTS1, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF3, AGPAT4, AKAP3, ANK1, ANK3, ANKRA2, ANKRD33B, ANKRD36, AP4B1-AS1, APIP, ARHGAP1, ARHGAP12, ARHGEF16, ARID5B, ARL15, ARL9, ARMCX6, ASIC1, ATG5, ATP2A3, ATXN1, B3GALT2, B3GNT6, BCL2L15, BCYRN1, BECN1, BHMT2, BIN3-IT1, BIRC3, BIRC6, BTG2, BTN3A1, C10orf54, C11orf70, C11orf94, C12orf4, C12orf56, C14orf132, C19orf47, C1orf86, C3, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, CA13, CA3, CACNA2D2, CACNB1, CADM1, CAND2, CASP7, CCDC122, CCDC79, CCER2, CCNF, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP170, CEP192, CFH, CHEK1, CIITA, CLDN23, CLTA, CMAHP, CNGA4, CNRIP1, CNTD1, COL11A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A6, COL8A1, COLEC12, COMP, CPA4, CPQ, CPSF4, CRISPLD2, CRLF1, CRYBG3, CRYL1, CSNK1E, CSNK1G1, CYB5R2, CYGB, CYP1B1, DAGLB, DCAF17, DCLK1, DCN, DDIT4L, DDX50, DEGS1, DEPTOR, DFNB59, DIRAS3, DLG5, DLGAP4, DNAH8, DNAJC13, DNAJC27, DNMBP, DOCK11, DYNC1I1, DYRK1A, DZIP1L, EFEMP1, EGR3, ELN, ELP4, EMX2OS, ENAH, ENPP1, EP300, ERCC1, ERCC8, ERGIC3, ERLIN2, ERRFI1, ESM1, EVC, EVC2, F2R, FAIM, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM20A, FAM46B, FAM65B, FAP, FARP1, FBLN2, FBN2, FBXL6, FCHO1, FGFR2, FGL2, FLT1, FRAS1, FSCN2, GAL3ST4, GALNT15, GATA6, GBGT1, GCNT1, GDF6, GGACT, GLCE, GNAQ, GPR183, GPR50, GPRC5A, GPRC5B, GRTP1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS3, HAVCR2, HDAC5, HDX, HECTD2-AS1, HEPH, HEY1, HMGA2, HMGN3-AS1, HNMT, HOOK3, HPS1, HSPA1L, HTATIP2, IFT57, IGDCC4, IGF2R, IGFBP3, IL16, INA, INPP5K, INTU, IQCG, ITGA11, ITGA8, ITGB8, ITIH1, ITPKA, IVD, KAT6B, KCNS1, KCNS2, KDM6A, KDSR, KIAA1456, KIAA1462, KIAA1755, KIT, KLF17, KLRG1, KMT2D, KRT7, KRTAP1-1, KRTAP1-5, L3MBTL2, LAMB2P1, LETM2, LGI2, LGR4, LHX9, LINC00472, LINC00570, LINC00578, LINC00607, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LMOD1, LOC400927, LRBA, LRP4, LRRC32, LRRC39, LRRC42, LSAMP, LUM, LYPD1, LYRM1, MAFB, MAMDC2, MAN2A1, MAN2C1, MAPK13, MASP1, MB, MB21D2, MC4R, MCM10, MED13L, MEGF6, MFN2, MIAT, MIR612, MLLT10, MMP10, MMP24, MN1, MOXD1, MRPL45, MRPL55, MRPS28, MRVI1, MSH4, MTERF3, MXRA5, MYCBP2, NA, NAALADL2, NAE1, NAGS, NDNF, NGF, NGFR, NHLH1, NLN, NOTCH3, NOTUM, NOVA2, NOX4, NRROS, OCLN, OLR1, OSBPL10, OXCT1, OXCT2, PAIP2B, PBLD, PDE1C, PDE5A, PDGFD, PDGFRB, PDS5B, PEAR1, PHACTR3, PIGN, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNM3, PLEK2, PLEKHA1, PLEKHA6, PLEKHH2, PLSCR1, PNISR, PODN, POLN, POLR1A, POMT2, PPARG, PPIP5K2, PPM1E, PPPR26, PPP3CA, PRKCA, PRKG1, PRPF31, PRPH2, PRRG4, PRUNE2, PSMD6-AS2, PTGIS, PTX3, PXK, RAB30, RAB38, RAB44, RAD9B, RAF1, RAPGEF1, RARS, RARS2, RBBP8, RBKS, RDX, RERE, RFX3-AS1, RGCC, ROR1, ROR2, RPA1, RPS10, RPS6KB2, SAMD4A, SCARNA9, SEC24A, SENP6, SERGEF, SGK3, SH3YL1, SHROOM3, SIGLEC10, SKA2, SLC12A2, SLC24A3, SLC35F3, SLC39A10, SLC44A2, SLC46A2, SLC4A11, SLC6A15, SLC7A11, SLC9A3, SLIT3, SMG1P3, SMTN, SNED1, SNX7, SORBS2, SORCS2, SOX7, SPATA18, SPATA5, SPDYA, SPEF2, SPIDR, SPRYD7, SRGAP1, SRRM1, STAC2, STAT4, STK32B, STRN4, STS, STXBP6, SULF1, SVEP1, SYNGR2, SYNPO, SYNPO2, SYNPO2L, TAGLN3, TANGO6, TASP1, TCF12, TCF4, TGFA, TGFB2, TGFB3, TGM2, THBS2, TIAM1, TMC3, TMEM102, TMEM119, TMEM134, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM50B, TNFAIP8L3, TNFRSF14, TNRC18P1, TNRC6A, TNXB, TP53AIP1, TPRG1, TRIM66, TRPC4, TSHZ2, TSPAN11, TSPAN18, TSPAN7, TSSK3, TTC7B, TUBE1, TXNIP, TYW5, URGCP, USP27X, UVRAG, VAV2, VIM-AS1, VPS41, VSTM2L, VWF, WDR27, WDR91, WISP1, WNK1, WNT10B, YDJC, ZBTB26, ZCCHC5, ZCCHC8, ZFP82, ZMIZ1-AS1, ZNF138, ZNF212, ZNF232, ZNF350, ZNF431, ZNF660, ZNF680, ZNF79, and ZNF837.
(297) In a particular aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting a cell or cell lysate containing the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from ABCA10, ABCB8, ABCC3, ACTA2, ADAL, ADAMTS1, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF3, AGPAT4, AKAP3, ANK1, ANK3, ANKRA2, ANKRD33B, ANKRD36, AP4B1-AS1, APIP, ARHGAP1, ARHGAP12, ARHGEF16, ARID5B, ARL15, ARL9, ARMCX6, ASIC1, ATG5, ATP2A3, ATXN1, B3GALT2, B3GNT6, BCL2L15, BCYRN1, BECN1, BHMT2, BIN3-IT1, BIRC3, BIRC6, BTG2, BTN3A1, C10orf54, C11orf70, C11orf94, C12orf4, C12orf56, C14orf132, C19orf47, C1orf86, C3, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, CA13, CA3, CACNA2D2, CACNB1, CADM1, CAND2, CASP7, CCDC122, CCDC79, CCER2, CCNF, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP170, CEP192, CFH, CHEK1, CIITA, CLDN23, CLTA, CMAHP, CNGA4, CNRIP1, CNTD1, COL11A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A6, COL8A1, COLEC12, COMP, CPA4, CPQ, CPSF4, CRISPLD2, CRLF1, CRYBG3, CRYL1, CSNK1E, CSNK1G1, CYB5R2, CYGB, CYP1B1, DAGLB, DCAF17, DCLK1, DCN, DDIT4L, DDX50, DEGS1, DEPTOR, DFNB59, DIRAS3, DLG5, DLGAP4, DNAH8, DNAJC13, DNAJC27, DNMBP, DOCK11, DYNC1I1, DYRK1A, DZIP1L, EFEMP1, EGR3, ELN, ELP4, EMX2OS, ENAH, ENPP1, EP300, ERCC1, ERCC8, ERGIC3, ERLIN2, ERRFI1, ESM1, EVC, EVC2, F2R, FAIM, FAM126A, FAM13A, FAM160A, FAM162A, FAM174A, FAM20A, FAM46B, FAM65B, FAP, FARP1, FBLN2, FBN2, FBXL6, FCHO1, FGFR2, FGL2, FLT1, FRAS1, FSCN2, GAL3ST4, GALNT15, GATA6, GBGT1, GCNT1, GDF6, GGACT, GLCE, GNAQ, GPR183, GPR50, GPRC5A, GPRC5B, GRTP1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS3, HAVCR2, HDAC5, HDX, HECTD2-AS1, HEPH, HEY1, HMGA2, HMGN3-AS1, HNMT, HOOK3, HPS1, HSPA1L, HTATIP2, IFT57, IGDCC4, IGF2R, IGFBP3, IL16, INA, INPP5K, INTU, IQCG, ITGA11, ITGA8, ITGB8, ITIH1, ITPKA, IVD, KAT6B, KCNS1, KCNS2, KDM6A, KDSR, KIAA1456, KIAA1462, KIAA1755, KIT, KLF17, KLRG1, KMT2D, KRT7, KRTAP1-1, KRTAP1-5, L3MBTL2, LAMB2P1, LETM2, LGI2, LGR4, LHX9, LINC00472, LINC00570, LINC00578, LINC00607, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LMOD1, LOC400927, LRBA, LRP4, LRRC32, LRRC39, LRRC42, LSAMP, LUM, LYPD1, LYRM1, MAFB, MAMDC2, MAN2A1, MAN2C1, MAPK13, MASP1, MB, MB21D2, MC4R, MCM10, MED13L, MEGF6, MFN2, MIAT, MIR612, MLLT10, MMP10, MMP24, MN1, MOXD1, MRPL45, MRPL55, MRPS28, MRVI1, MSH4, MTERF3, MXRA5, MYCBP2, NA, NAALADL2, NAE1, NAGS, NDNF, NGF, NGFR, NHLH1, NLN, NOTCH3, NOTUM, NOVA2, NOX4, NRROS, OCLN, OLR1, OSBPL10, OXCT1, OXCT2, PAIP2B, PBLD, PDE1C, PDE5A, PDGFD, PDGFRB, PDS5B, PEAR1, PHACTR3, PIGN, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNM3, PLEK2, PLEKHA1, PLEKHA6, PLEKHH2, PLSCR1, PNISR, PODN, POLN, POLR1A, POMT2, PPARG, PPIP5K2, PPM1E, PPP1R26, PPP3CA, PRKCA, PRKG1, PRPF31, PRPH2, PRRG4, PRUNE2, PSMD6-AS2, PTGIS, PTX3, PXK, RAB30, RAB38, RAB44, RAD9B, RAF1, RAPGEF1, RARS, RARS2, RBBP8, RBKS, RDX, RERE, RFX3-AS1, RGCC, ROR1, ROR2, RPA1, RPS10, RPS6KB2, SAMD4A, SCARNA9, SEC24A, SENP6, SERGEF, SGK3, SH3YL1, SHROOM3, SIGLEC10, SKA2, SLC12A2, SLC24A3, SLC35F3, SLC39A10, SLC44A2, SLC46A2, SLC4A11, SLC6A15, SLC7A11, SLC9A3, SLIT3, SMG1P3, SMTN, SNED1, SNX7, SORBS2, SORCS2, SOX7, SPATA18, SPATA5, SPDYA, SPEF2, SPIDR, SPRYD7, SRGAP1, SRRM1, STAC2, STAT4, STK32B, STRN4, STS, STXBP6, SULF1, SVEP1, SYNGR2, SYNPO, SYNPO2, SYNPO2L, TAGLN3, TANGO6, TASP1, TCF12, TCF4, TGFA, TGFB2, TGFB3, TGM2, THBS2, TIAM1, TMC3, TMEM102, TMEM119, TMEM134, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM50B, TNFAIP8L3, TNFRSF14, TNRC18P1, TNRC6A, TNXB, TP53AIP1, TPRG1, TRIM66, TRPC4, TSHZ2, TSPAN11, TSPAN18, TSPAN7, TSSK3, TTC7B, TUBE1, TXNIP, TYW5, URGCP, USP27X, UVRAG, VAV2, VIM-AS1, VPS41, VSTM2L, VWF, WDR27, WDR91, WISP1, WNK1, WNT10B, YDJC, ZBTB26, ZCCHC5, ZCCHC8, ZFP82, ZMIZ1-AS1, ZNF138, ZNF212, ZNF232, ZNF350, ZNF431, ZNF660, ZNF680, ZNF79, and ZNF837. In some aspects, the intron further comprises a first 5′ splice site, a second branch point, and a second 3′ splice site upstream of the iREMS.
(298) In a particular aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting a cell or cell lysate containing the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM12, ADAM15, ADAM17, ADAM23, ADAM33, ADAMTS1, ADAMTS19, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP8L, AKAP9, AKNA, AKT1, ALCAM, ALDH4A1, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD13C, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APLP2, APOA2, APP, APPL2, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGAP5, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARL5B, ARMCX3, ARMCX6, ARSJ, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF6, ATF7IP, ATG5, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, AXIN1, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3, BIN3-IT1, BIRC3, BIRC6, BNC1, BNC2, BRCA1, BRCA2, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1QTNF9B-AS1, C1orf27, C1orf86, C10orf54, C11orf30, C11orf170, C1orf73, C11orf76, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C2orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CACNB4, CADM1, CADM2, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCNL2, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDH18, CDK11B, CDK16, CDKAL1, CDKN1C, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP162, CEP170, CEP192, CEP57, CEP68, CFH, CFLAR, CHD8, CHEK1, CHRM2, CITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, CMSS1, CNOT7, CNRIP1, CNTN1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRX, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CTRC, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAAM1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND4A, DENND5A, DEPTOR, DET1, DFNB59, DGCR2, DGK1, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DLGAP4, DMD, DMXL1, DNAH8, DNAH11, DNAJA4, DNAJC13, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEF1A1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELMO2, ELN, ELP4, EMX2OS, ENAH, ENG, ENOX1, ENPP1, ENPP2, ENSA, EP300, EPN1, EPT1, ERC1, ERC2, ERCC1, ERCC8, ERGIC3, ERLIN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXOC3, EXOC6B, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM195B, FAM198B, FAM20A, FAM208B, FAM219A, FAM219B, FAM3C, FAM46B, FAM49B, FAM65A, FAM65B, FAM69B, FAP, FARP1, FBLN2, FBN2, FBXL16, FBXL6, FBXO9, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD4, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GBP1, GCFC2, GLCE, GCNT1, GDF6, GGACT, GGCT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNG12, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GTSF1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HMGXB4, HOOK3, HOXB3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSD17B4, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IKBKAP, IL16, IL6ST, INA, INHBA, INO80, IPP4B, INPP5K, INSIG1, INTU, INVS, IQCE, IQCG, ITCH, ITGAI1, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIDINS220, KIF14, KIF2A, KIF21A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LARP7, LATS2, LDLR, LEMD3, LETM2, LGALS3, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, LINC00578, LINC00607, LINC00657, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LINCR-0002, LINGO2, LMAN2L, LMNA, LMO7, LMOD1, LOC400927, LONP1, LOX, LPHN1, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC1, LRRC32, LRRC39, LRRC42, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MACROD2, MADD, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MANEA, MAP4K4, MAPK10, MAPK13, MARCH7, MARCH8, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MDN1, MEAF6, MECP2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MORF4L1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL39, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR3, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYB, MYCBP2, MYLK, MYO1D, MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NEDD4, NELFA, NEO1, NEURL1B, NF2, NFASC, NFE2L1, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLGN1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL3, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PAX6, PBLD, PBX3, PCBP2, PCBP4, PCCB, PCDH10, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE3A, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PDXDC2P, PEAR1, PELI1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPFIBP1, PPHLN1, PPIP5K1, PPIP5K2, PPM1E, PPP1R12A, PPP1R26, PPP3CA, PPP6R1, PPP6R2, PRKACB, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTCH1, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB23, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAP1A, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASIP1, RASSF8, RBBP8, RBCK1, RCOR3, RBFOX2, RBKS, RBM10, RCC1, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGL1, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF130, RNF144A, RNF213, RNF38, RNFT1, ROR1, ROR2, RPA1, RPF2, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A1, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SF3B3, SGIP1, SGK3, SGMS1, SGOL2, SGPL1, SH2B3, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SKP1, SLC12A2, SLC24A3, SLC25A16, SLC25A17, SLC34A3, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMN2, SMOX, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SNX24, SNX7, SOCS2, SOCS6, SOGA2, SON, SORBS2, SORCS1, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPINK5, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRGAP1, SRRM1, SRSF3, SSBP1, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRAD8, STRIP1, STRN3, STRN4, STS, STX16, STXBP4, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBCA, TBL1XR1, TBL2, TCF12, TCF4, TCF7L2, TEKT4P2, TENC1, TENM2, TEP1, TET1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFB1, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJAP1, TJP2, TLE3, TLK1, TMC3, TMEM67, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TMX3, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNRC6A, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNL4B, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2D3, UBE2G2, UBE2L3, UBE2V1, UBN2, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC13B, UNC5B, URGCP, URGCP-MRPS24, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VDAC2, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR90, WDR91, WHSC2, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XDH, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMIZ2, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF208, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF280D, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF426, ZNF431, ZNF583, ZNF618, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF730, ZNF74, ZNF764, ZNF777, ZNF778, ZNF780A, ZNF7804A, ZNF79, ZNF827, ZNF836, ZNF837, ZNF839, ZNF91 and ZSCAN25.
(299) In a particular aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting a cell or cell lysate containing the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from APOA2, ASAP1, BRCA1, BRCA2, CDKN1C, CRX, CTRC, DENND5A, DIAPH3, DMD, DNAH11, EIF2B3, GALC, HPS1, HTT, IKBKAP, KIAA1524, LMNA, MECP2, PAPD4, PAX6, PCCB, PITPNB, PTCH1, SLC34A3, SMN2, SPINK5, SREK1, TMEM67, VWF, XDH and XRN2.
(300) In a particular aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting a cell or cell lysate containing the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is selected from ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM15, ADAM17, ADAM23, ADAM33, ADAMTS1, ADAMTS19, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP8L, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD13C, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APOA2, APP, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGAP5, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARL5B, ARMCX3, ARSJ, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF6, ATF7IP, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3, BIN3-IT1, BIRC3, BIRC6, BNC1, BNC2, BRCA1, BRCA2, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1QTNF9B-AS1, C1orf27, C1orf86, C10orf54, C11orf30, C11orf70, C11orf73, C11orf76, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C2orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf8, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CACNB4, CADM1, CADM2, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCNL2, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDH18, CDK11B, CDK16, CDKAL1, CDKN1C, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP162, CEP170, CEP192, CEP68, CFH, CFLAR, CHD8, CHEK1, CHRM2, CIITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, CMSS1, CNOT7, CNRIP1, CNTN1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRX, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CTRC, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAAM1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND4A, DENND5A, DEPTOR, DET1, DFNB59, DGCR2, DGK1, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DMD, DMXL1, DNAH8, DNAH11, DNAJA4, DNAJC13, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEF1A1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELMO2, ELN, ELP4, EMX2OS, ENAH, ENG, ENOX1, ENPP1, ENPP2, ENSA, EP300, EPT1, ERC1, ERC2, ERCC1, ERCC8, ERLIN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXOC3, EXOC6B, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM26A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM195B, FAM198B, FAM20A, FAM208B, FAM219A, FAM219B, FAM3C, FAM46B, FAM49B, FAM65A, FAM65B, FAM69B, FAP, FARP1, FBLN2, FBN2, FBXL16, FBXL6, FBXO9, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD4, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GBP1, GCFC2, GLCE, GCNT1, GDF6, GGACT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNG12, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GTSF1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HMGXB4, HOOK3, HOXB3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IKBKAP, IL16, IL6ST, INA, INHBA, INO80, IPP4B, INPP5K, INSIG1, INTU, INVS, IQCE, IQCG, ITCH, ITGAI1, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIDINS220, KIF14, KIF2A, KIF21A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LATS2, LDLR, LEMD3, LETM2, LGALS3, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, LINC00578, LINC00607, LINC00657, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LINCR-0002, LINGO2, LMAN2L, LMNA, LMO7, LMOD1, LOC400927, LONP1, LOX, LPHN1, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC1, LRRC32, LRRC39, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MACROD2, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MANEA, MAP4K4, MAPK10, MAPK13, MARCH7, MARCH8, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MDN1, MEAF6, MECP2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MORF4L1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR3, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYB, MYCBP2, MYLK, MYO1D, MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NEDD4, NELFA, NEO1, NEURL1B, NF2, NFASC, NFE2L1, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLGN1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL3, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PAX6, PBLD, PBX3, PCBP2, PCCB, PCDH10, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE3A, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PDXDC2P, PEARL PELI1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPFIBP1, PPIP5K1, PPIP5K2, PPM1E, PPP1R12A, PPPR26, PPP3CA, PPP6R1, PPP6R2, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTCH1, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASIP1, RASSF8, RBBP8, RBCK1, RCOR3, RBFOX2, RBKS, RBM10, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGL1, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF130, RNF144A, RNF213, RNF38, RNFT1, ROR1, ROR2, RPA1, RPF2, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A1, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SF3B3, SGIP1, SGK3, SGMS1, SGOL2, SGPL1, SH2B3, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SKP1, SLC12A2, SLC24A3, SLC25A16, SLC25A17, SLC34A3, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMOX, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SNX24, SNX7, SOCS2, SOCS6, SOGA2, SON, SORBS2, SORCS1, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPINK5, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SRGAP1, SRRM1, SRSF3, SSBP1, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRAD8, STRIP1, STRN4, STS, STX16, STXBP4, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBCA, TBL1XR1, TBL2, TCF12, TCF4, TCF7L2, TEKT4P2, TENC1, TENM2, TEP1, TET1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFB1, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJAP1, TJP2, TLE3, TLK1, TMC3, TMEM67, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TMX3, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNL4B, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2D3, UBE2G2, UBE2L3, UBE2V1, UBN2, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC13B, UNC5B, URGCP, URGCP-MRPS24, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VDAC2, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR90, WDR91, WHSC2, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XDH, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMIZ2, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF208, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF280D, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF426, ZNF431, ZNF583, ZNF618, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF730, ZNF74, ZNF764, ZNF777, ZNF778, ZNF780A, ZNF7804A, ZNF79, ZNF827, ZNF836, ZNF837, ZNF839, ZNF91 and ZSCAN25.
(301) In a particular aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting a cell or cell lysate containing the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is not SMN2.
(302) In a particular aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting a cell or cell lysate containing the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is not selected from ABHD10, ADAM12, AKT1, ANXA11, APLP2, APPL2, ARMCX6, ATG5, AXIN1, BAIAP2, CCNB1IP1, CCT7, CEP57, CSF1, DLGAP4, EPN1, ERGIC3, FOXM1, GGCT, GRAMD3, HSD17B4, LARP7, LRRC42, MADD, MAN1B1, MRPL39, PCBP4, PPHLN1, PRKACB, RAB23, RAP1A, RCC1, SREK1, STRN3 and TNRC6A.
(303) In a particular aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a mature mRNA transcript produced by a pre-mRNA transcript, the method comprising contacting a cell or cell lysate containing the pre-mRNA transcript with a compound of Formula (I) or a form thereof, wherein the pre-mRNA transcript comprises two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the intron comprises a RNA nucleotide sequence comprising in 5′ to 3′ order: an endogenous or non-endogenous intronic recognition element for splicing modifier (iREMS), a branch point, and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, wherein r is adenine or guanine and n is any nucleotide, and wherein the pre-mRNA transcript is a pre-mRNA transcript of a gene that is not selected from ABHD10, ADAM12, AKT1, ANXA11, APLP2, APPL2, ARMCX6, ATG5, AXIN1, BAIAP2, CCNB1IP1, CCT7, CEP57, CSF1, DLGAP4, EPN1, ERGIC3, FOXM1, GGCT, GRAMD3, HSD17B4, LARP7, LRRC42, MADD, MAN1B1, MRPL39, PCBP4, PPHLN1, PRKACB, RAB23, RAP1A, RCC1, SMN2, SREK1, STRN3 and TNRC6A.
(304) In certain aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is primary cell(s) or cell(s) from a cell line. In some aspects, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a fibroblast(s), an immune cell(s), or a muscle cell(s). In some embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell. Non-limiting examples of cell lines include 3T3, 4T1, 721, 9L, A2780, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1, BEAS-2B, bEnd.3, BHK, BR 293, BT20, BT483, BxPC3, C2C12, C3H-10T1/2, C6/36, C6, Cal-27, CHO, COR-L23, COS, COV-434, CML T1, CMT, CRL7030, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299, H69, HB54, HB55, HCA2, HD-1994, HDF, HEK-293, HeLa, Hepa1c1c7, HL-60, HMEC, Hs578T, HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22, KG1, KYO1, LNCap, Ma-Mel, MC-38, MCF-7, MCF-10A, MDA-MB-231, MDA-MB-468, MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69, NIH-3T3, NALM-1, NSO, NW-145, OPCN, OPCT, PNT-1A, PNT-2, Raji, RBL, RenCa, RIN-5F, RMA, Saos-2, Sf21, Sf9, SH-SY5Y, SiHa, SKBR3, SKOV-3, T2, T-47D, T84, THP1, U373, U87, U937, VCaP, Vero, VERY, W138, WM39, WT-49, X63, YAC-1, and YAR cells. In one aspect, the cells are from a patient. In another aspect, the patient cells are GM03813 cells. In another aspect, the patient cells are GM04856, GM04857, GM09197, GM04281, GM04022, GM07492 cells.
(305) In certain aspects described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof with a compound of Formula (I) or a form thereof for a period of 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72 hours or more. In other aspects described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof with a compound of Formula (I) or a form thereof for a period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12 hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24 to 48 hours, 48 to 72 hours.
(306) In certain aspects described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 0.01 μM, 0.05 μM, 1 μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM, 25 μM, 50 μM, 75 μM, 100 μM, or 150 μM. In other aspects described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 175 μM, 200 μM, 250 μM, 275 μM, 300 μM, 350 μM, 400 μM, 450 μM, 500 μM, 550 μM, 600 μM, 650 μM, 700 μM, 750 μM, 800 μM, 850 μM, 900 μM, 950 μM or 1 mM. In some aspects described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, or 950 nM. In certain aspects described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is between 0.01 μM to 0.1 μM, 0.1 μM to 1 μM, 1 μM to 50 μM, 50 μM to 100 μM, 100 μM to 500 μM, 500 μM to 1 nM, 1 nM to 10 nM, 10 nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM. In certain aspects described herein, the cell(s) is contacted or cultured with a certain concentration of a compound of Formula (I) or a form thereof that results in a substantial change in the amount of an RNA transcript (e.g., an mRNA transcript), an alternatively spliced variant, or an isoform of a gene (e.g., a gene described herein, infra).
(307) In another aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(308) In one aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene described herein, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
(309) In another aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene described herein, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(310) In a particular aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene in a subject, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS (for example, an endogenous intronic REMS or a non-endogenous intronic REMS), the methods comprising administering to the subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent, and wherein the gene is selected from ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM12, ADAM15, ADAM17, ADAM23, ADAM33, ADAMTS1, ADAMTS19, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP8L, AKAP9, AKNA, AKT1, ALCAM, ALDH4A1, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD13C, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APLP2, APOA2, APP, APPL2, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGAP5, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARL5B, ARMCX3, ARMCX6, ARSJ, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF6, ATF7IP, ATG5, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, AXIN1, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3, BIN3-IT1, BIRC3, BIRC6, BNC1, BNC2, BRCA1, BRCA2, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1QTNF9B-AS1, C1orf27, C1orf86, C10orf54, C11orf30, C11orf70, C11orf73, C11orf76, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C2orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CACNB4, CADM1, CADM2, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCNL2, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDH18, CDK11B, CDK16, CDKAL1, CDKN1C, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP162, CEP170, CEP192, CEP57, CEP68, CFH, CFLAR, CHD8, CHEK1, CHRM2, CIITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, CMSS1, CNOT7, CNRIP1, CNTN1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRX, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CTRC, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAAM1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND4A, DENND5A, DEPTOR, DET1, DFNB59, DGCR2, DGK1, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DLGAP4, DMD, DMXL1, DNAH8, DNAH11, DNAJA4, DNAJC13, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEFIA1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELMO2, ELN, ELP4, EMX2OS, ENAH, ENG, ENOX1, ENPP1, ENPP2, ENSA, EP300, EPN1, EPT1, ERC1, ERC2, ERCC1, ERCC8, ERGIC3, ERLIN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXOC3, EXOC6B, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM195B, FAM198B, FAM20A, FAM208B, FAM219A, FAM219B, FAM3C, FAM46B, FAM49B, FAM65A, FAM65B, FAM69B, FAP, FARP1, FBLN2, FBN2, FBXL16, FBXL6, FBXO9, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD4, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GBP1, GCFC2, GLCE, GCNT1, GDF6, GGACT, GGCT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNG12, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GTSF1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HMGXB4, HOOK3, HOXB3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSD17B4, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IKBKAP, IL16, IL6ST, INA, INHBA, INO80, IPP4B, INPP5K, INSIG1, INTU, INVS, IQCE, IQCG, ITCH, ITGA11, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIDINS220, KIF14, KIF2A, KIF21A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LARP7, LATS2, LDLR, LEMD3, LETM2, LGALS3, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, LINC00578, LINC00607, LINC00657, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LINCR-0002, LINGO2, LMAN2L, LMNA, LMO7, LMOD1, LOC400927, LONP1, LOX, LPHN1, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC1, LRRC32, LRRC39, LRRC42, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MACROD2, MADD, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MANEA, MAP4K4, MAPK10, MAPK13, MARCH7, MARCH8, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MDN1, MEAF6, MECP2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MORF4L1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL39, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR3, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYB, MYCBP2, MYLK, MYO1D, MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NEDD4, NELFA, NEO1, NEURL1B, NF2, NFASC, NFE2L1, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLGN1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL3, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PAX6, PBLD, PBX3, PCBP2, PCBP4, PCCB, PCDH10, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE3A, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PDXDC2P, PEAR1, PELI1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPFIBP1, PPHLN1, PPIP5K1, PPIP5K2, PPM1E, PPP1R12A, PPP1R26, PPP3CA, PPP6R1, PPP6R2, PRKACB, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTCH1, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB23, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAP1A, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASIP1, RASSF8, RBBP8, RBCK1, RCOR3, RBFOX2, RBKS, RBM10, RCC1, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGL1, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF130, RNF144A, RNF213, RNF38, RNFT1, ROR1, ROR2, RPA1, RPF2, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A1, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SF3B3, SGIP1, SGK3, SGMS1, SGOL2, SGPL1, SH2B3, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SKP1, SLC12A2, SLC24A3, SLC25A16, SLC25A17, SLC34A3, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMN2, SMOX, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SNX24, SNX7, SOCS2, SOCS6, SOGA2, SON, SORBS2, SORCS1, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPINK5, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRGAP1, SRRM1, SRSF3, SSBP1, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRAD8, STRIP1, STRN3, STRN4, STS, STX16, STXBP4, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBCA, TBL1XR1, TBL2, TCF12, TCF4, TCF7L2, TEKT4P2, TENC1, TENM2, TEP1, TET1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFB1, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJAP1, TJP2, TLE3, TLK1, TMC3, TMEM67, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TMX3, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNRC6A, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNL4B, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2D3, UBE2G2, UBE2L3, UBE2V1, UBN2, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC13B, UNC5B, URGCP, URGCP-MRPS24, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VDAC2, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR90, WDR91, WHSC2, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XDH, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMIZ2, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF208, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF280D, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF426, ZNF431, ZNF583, ZNF618, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF730, ZNF74, ZNF764, ZNF777, ZNF778, ZNF780A, ZNF7804A, ZNF79, ZNF827, ZNF836, ZNF837, ZNF839, ZNF91 and ZSCAN25.
(311) In a specific aspect of the foregoing, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect of the foregoing, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect of the foregoing, the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(312) In another specific aspect of the foregoing, the gene is selected from ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM12, ADAM15, ADAM17, ADAM33, ADAMTS1, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APLP2, APP, APPL2, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARMCX3, ARMCX6, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF7IP, ATG5, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, AXIN1, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3-IT1, BIRC3, BIRC6, BNC1, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1orf86, C10orf54, C11orf30, C11orf70, C11orf73, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CADM1, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDK11B, CDK16, CDKAL1, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP170, CEP192, CEP68, CFH, CFLAR, CHD8, CHEK1, CIITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND5A, DEPTOR, DFNB59, DGCR2, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DLGAP4, DNAH8, DNAJC13, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEFIA1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELN, ELP4, EMX2OS, ENAH, ENG, ENPP1, ENPP2, ENSA, EP300, EPN1, EPT1, ERC1, ERCC1, ERCC8, ERGIC3, ERLIN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM198B, FAM20A, FAM219A, FAM219B, FAM3C, FAM46B, FAM65A, FAM65B, FAP, FARP1, FBLN2, FBN2, FBXO9, FBXL6, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GCFC2, GCNT1, GDF6, GGACT, GGCT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HOOK3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSD17B4, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IL16, IL6ST, INA, INHBA, INPP5K, INSIG1, INTU, IQCE, IQCG, ITGA11, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIF14, KIF2A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LARP7, LATS2, LDLR, LEMD3, LETM2, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, LINC00578, LINC00607, LINC00657, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LMAN2L, LMO7, LMOD1, LOC400927, LONP1, LOX, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC32, LRRC39, LRRC42, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MADD, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MAP4K4, MAPK13, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYCBP2, MYLK, MYO1D, MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NELFA, NEO1, NEURL1B, NF2, NFE2L1, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PBLD, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PEAR1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPHLN1, PPIP5K1, PPIP5K2, PPM1E, PPP1R12A, PPP1R26, PPP3CA, PPP6R1, PPP6R2, PRKACB, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB23, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAP1A, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASSF8, RBBP8, RBCK1, RBFOX2, RBKS, RBM10, RCC1, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF38, RNFT1, ROR1, ROR2, RPA1, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A1, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SGK3, SGOL2, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SLC12A2, SLC24A3, SLC25A17, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMN2, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SOCS2, SON, SORBS2, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRGAP1, SRRM1, SRSF3, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRIP1, STRN3, STRN4, STS, STX16, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBL2, TCF12, TCF4, TCF7L2, TENC1, TENM2, TEP1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFB1, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJP2, TLE3, TLK1, TMC3, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNRC6A, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2G2, UBE2V1, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC5B, URGCP, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR91, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF431, ZNF583, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF74, ZNF764, ZNF778, ZNF780A, ZNF79, ZNF827, ZNF837, ZNF839 and ZNF91.
(313) In another specific aspect of the foregoing, the gene is selected from ABCA1, ABCB7, ABCC1, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ADAM12, ADAM15, ADAM17, ADAM33, AFF2, AGK, AGPAT3, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK2, ANKFY1, ANKHD1-EIF4EBP3, ANKRD17, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, APAF1, APLP2, APP, APPL2, APTX, ARHGAP22, ARID1A, ARID2, ARMCX3, ASAP1, ASL, ASNS, ASPH, ATAD2B, ATF7IP, ATG9A, ATMIN, ATP2C1, ATXN3, AURKA, AXIN1, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BEND6, BICD1, BIN1, BNC1, BRD2, BRPF1, BSCL2, BTBD10, BZW1, C11orf30, C11orf73, C17orf76-AS1, C4orf27, C5orf24, C6orf48, C9orf69, CAB39, CALU, CAMKK1, CAPNS1, CASC3, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC88A, CCDC92, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDK11B, CDK16, CDKAL1, CEP68, CFLAR, CHD8, CIZ1, CLIC1, CLK4, CNOT1, COG1, COL12A1, COL1A1, COL6A1, COPS7B, CPEB2, CREB5, CRLS1, CRTAP, CSDE1, CSNK1A1, CTDSP2, CTNND1, CUL2, CUL4A, CUX1, CYB5B, CYBRD1, CYP51A1, DAB2, DACT1, DARS, DAXX, DCAF10, DCAF11, DCBLD2, DCUN1D4, DDAH1, DDAH2, DDHD2, DDR1, DDX39B, DDX42, DENND1A, DENND1B, DENND5A, DGCR2, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIS3L, DKFZp434M1735, DKK3, DLC1, DNM2, DOCK1, DPP8, DSEL, DST, DSTN, EBF1, EEA1, EEF1A1, EFCAB14, EGR1, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ENG, ENPP2, ENSA, EPN1, EPT1, ERC1, ERGIC3, ETV5, EXO1, EXTL2, EYA3, FADS1, FADS2, FAF1, FAM111A, FAM198B, FAM219A, FAM219B, FAM3C, FAM65A, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FDFT1, FDPS, FER, FEZ1, FGD5-AS1, FGFRL1, FHOD3, FLII, FLNB, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FUS, FYN, GABPB1, GALC, GALNT1, GAS7, GBA2, GCFC2, GGCT, GHDC, GIGYF2, GJC1, GMIP, GNA13, GNAS, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR89A, GPSM2, GREM1, GRK6, GSE1, GTF2H2B, HAS2, HAT1, HAUS3, HAUS6, HDAC7, HEG1, HLA-A, HLA-E, HLTF, HMGA1, HMGB1, HMGCR, HMGCS1, HMOX1, HNRNPR, HNRNPUL1, HP1BP3, HRH1, HSD17B12, HSD17B4, HTT, IARS, IDH1, IDI1, IGF2BP2, IL6ST, INHBA, INSIG1, IQCE, ITGAV, ITGB5, ITM2C, ITSN1, KANSL3, KCNK2, KIAA1033, KIAA1143, KIAA1199, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIF14, KIF2A, KIF3A, KLC1, KLC2, KLF6, KLHL7, KRT18, KRT19, KRT34, KRTAP2-3, LAMA2, LAMB1, LARP4 LARP7, LATS2, LDLR, LEMD3, LGALS8, LIMS1, LINC00341, LINC00657, LMAN2L, LMO7, LONP1, LOX, LRCH4, LRIG1, LRP8, LRRC8A, LSS, LTBR, LUC7L2, LZTS2, MADD, MAGED4, MAGED4B, MAN1A2, MAP4K4, MBD1, MBOAT7, MDM2, MED1, MEDAG, MEF2D, MEIS2, MEMO1, MEPCE, MFGE8, MICAL2, MINPP1, MKL1, MKLN1, MKNK2, MLLT4, MLST8, MMAB, MMS19, MMS22L, MPPE1, MPZL1, MRPL3, MSANTD3, MSC, MSH2, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERFD1, MTHFD1L, MTMR9, MTRR, MUM1, MVD, MVK, MYADM, MYLK, MYO1D, MYO9B, MYOF, NAA35, NADK, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NELFA, NEO1, NEURL1B, NF2, NFE2L1, NFX1, NID1, NID2, NIPA1, NKX3-1, NOL10, NOMO3, NPEPPS, NRD1, NREP, NRG1, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, ODF2, OS9, OSBPL6, OSMR, P4HA1, P4HB, PABPC1, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE4A, PDE7A, PDLIM7, PDXDC1, PEPD, PEX5, PFKP, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGU, PIK3C2B, PITPNA, PITPNB, PITPNM1, PLAU, PLEC, PLEKHB2, PLSCR3, PLXNB2, PLXNC1, PMS1, POLE3, POLR3D, POSTN, POU2F1, PPAPDC1A, PPARA, PPHLN1, PPIP5K1, PPPIR12A, PPP6R1, PPP6R2, PRKACB, PRKDC, PRMT1, PRNP, PRSS23, PSMA4, PSMC1, PSMD6, PTK2B, PTPN14, PUF60, PUS7, PVR, PXN, QKI, RAB23, RAB2B, RAB34, RAD1, RAD23B, RALB, RAP1A, RAP1GDS1, RARG, RASSF8, RBCK1, RBFOX2, RBM10, RCC1, RFTN1, RFWD2, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF38, RNFT1, RPL10, RPS6KC1, RRBP1, RWDD4, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24B, SEC61A1, SEPT9, SERPINE2, SF1, SGOL2, SH3RF1, SKIL, SLC25A17, SLC39A3, SLC41A1, SLC4A4, SLC7A6, SLC7A8, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMN2, SMPD4, SMYD3, SMYD5, SNAP23, SNHG16, SNX14, SOCS2, SON, SOS2, SPATA20, SPATS2, SPG20, SPRED2, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRSF3, STARD4, STAT1, STAT3, STAU1, STC2, STEAP2, STRIP1, STRN3, STX16, SUPT20H, SYNE1, SYNE2, SYT15, SYTL2, TACC1, TAF2, TANC2, TARBP1, TARS, TBC1D15, TBL2, TCF7L2, TENC1, TENM2, TEP1, TET3, TFCP2, TGFB1, TGFBR1, TGFBRAP1, THADA, THAP4, THRB, TIMP2, TJP2, TLE3, TLK1, TMEM154, TMEM47, TMEM63A, TNC, TNFAIP3, TNFRSF12A, TNIP1, TNKS1BP1, TNPO3, TNS1, TNS3, TOE1, TOMM40, TOMM5, TOPORS, TP53INP1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRMT1L, TRPS1, TSC2, TSHZ1, TSPAN2, TTC7A, TUBB2C, TUBB3, TXNL1, TXNRD1, U2SURP, UBAP2L, UBE2G2, UBE2V1, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC5B, USP19, USP7, VANGL1, VARS2, VCL, VIPAS39, VPS13A, VPS29, VPS51, VWA8, WDR19, WDR37, WDR48, WIPF1, WNT5B, WSB1, WWTR1, XIAP, XRN2, YAP1, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZHX3, ZMIZ1, ZMYM2, ZNF12, ZNF148, ZNF219, ZNF227, ZNF24, ZNF268, ZNF28, ZNF281, ZNF335, ZNF37A, ZNF37BP, ZNF395, ZNF583, ZNF621, ZNF652, ZNF655, ZNF674, ZNF74, ZNF764, ZNF778, ZNF780A, ZNF827, ZNF839 and ZNF91.
(314) In another specific aspect of the foregoing, the gene is selected from ABCB8, ANKRD36, APLP2, ARHGAP12, ARMCX6, ASAP1, ATG5, AXIN1, BIRC6, C1orf86, CDC42BPA, CLTA, DYRK1A, ERGIC3, FBXL6, FOXM1, GGCT, KAT6B, KDM6A, KIF3A, KMT2D, LARP7, LYRM1, MADD, MAN2C1, MRPL55, MYCBP2, MYO9B, PNISR, RAP1A, RAPGEF1, SENP6, SH3YL1, SLC25A17, SMN2, SREK1, STRN3, TAF2, TMEM134, VPS29, ZFAND1 and ZNF431.
(315) In another specific aspect of the foregoing, the gene is selected from ABCB8, ANKRD36, ARHGAP12, ARMCX6, ATG5, BIRC6, C1orf86, CLTA, DYRK1A, FBXL6, KAT6B, KDM6A, KMT2D, LYRM1, MAN2C1, MRPL55, MYCBP2, PNISR, RAPGEF1, SENP6, SH3YL1, TMEM134 and ZNF431.
(316) In another specific aspect of the foregoing, the gene is selected from ABCA10, ABCC1, ACTA2, ADAL, ADAM12, ADAMTS1, ADAMTS5, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPS, AKAP3, ANK1, ANK2, ANK3, ANKRD33B, ANXA11, ANXA6, AP4B1-AS1, ARHGEF16, ARID5B, ARL9, ARMCX3, ASAP1, ASIC1, ATP2A3, B3GALT2, B3GNT6, BCL2L15, BCYRN1, BIN3-IT, BIRC3, BTG2, C10orf54, C11orf70, C11orf73, C11orf94, C12orf56, C19orf47, C3, C4orf27, C7orf31, C8orf34, CA13, CA3, CACNA2D2, CACNB1, CADM1, CAND2, CCDC79, CCER2, CCNF, CDCA7, CDKAL1, CELSR1, CEMIP, CEP170, CFH, CIITA, CLDN23, CMAHP, CNGA4, CNTD1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A6, COL8A1, COLEC2, COMP, CPA4, CPQ, CRISPLD2, CRLF1, CRYL1, CUX1, CYB5B, CYB5R2, CYGB, CYP1B1, DCLK1, DCN, DDIT4L, DDX42, DDX50, DEGS1, DENND1A, DENND5A, DEPTOR, DFNB59, DGKA, DHFR, DIAPH3, DIRAS3, DIS3L, DLG5, DNAH8, DNAJC27, DOCK1, DOCK11, DYNC1I1, DZIP1L, EBF1, EFEMP1, EGR3, EIF2B3, ELN, ELP4, EMX2OS, ENPP1, ERCC8, ESM1, EVC2, F2R, FAM160A1, FAM198B, FAM20A, FAM46B, FAM65B, FAP, FARP1, FBLN2, FBN2, FBXO9, FCHO1, FER, FGFR2, FGL2, FLT1, FRAS1, FSCN2, GAL3ST4, GALC, GALNT15, GATA6, GBGT1, GCNT1, GDF6, GNAQ, GOLGB1, GPR183, GPR50, GPRC5A, GPRC5B, GRTP1, GUCA1B, GXYLT1, HAPLN1, HAPLN2, HAS3, HAVCR2, HDAC5, HECTD2-AS1, HEPH, HEY1, HLTF, HMGN3-AS1, HMOX1, HOOK3, HSD17B12, HSPA1L, HTATIP2, HTT, IGDCC4, IGF2R, IGFBP3, IL16, INA, INTU, IQCG, ITGA11, ITGA8, ITGB8, ITIH1, ITPKA, KCNS1, KCNS2, KDM6A, KDSR, KIAA1456, KIAA1462, KIAA1524, KIAA1715, KIAA1755, KIT, KLF17, KLRG1, KRT7, KRTAP1-1, KRTAP1-5, L3MBTL2, LAMB2P1, LGI2, LGR4, LHX9, LINC00472, LINC00570, LINC00578, LINC00607, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LMOD1, LRBA, LRP4, LRRC32, LRRC39, LSAMP, LUM, LYPD1, LYRM1, MAFB, MAMDC2, MAN1A2, MAN2A1, MAPK13, MASP1, MB, MC4R, MEDAG, MEGF6, MEMO1, MIAT, MIR612, MLLT10, MMP10, MMP24, MMS19, MN1, MOXD1, MRVI1, MSH4, MTERF3, MXRA5, MYO1D, NA, NAALADL2, NAE1, NAGS, NDNF, NEURL1B, NGFR, NHLH1, NLN, NOTCH3, NOTUM, NOVA2, NOX4, NRROS, NTNG1, OCLN, OLR1, OSBPL10, OXCT2, PAIP2B, PAPD4, PBLD, PCM1, PDE1C, PDE5A, PDGFD, PDGFRB, PDS5B, PDXDC1, PEAR1, PEPD, PHACTR3, PI4K2B, PIK3R1, PIM2, PITPNB, PITPNM3, PLAU, PLEK2, PLEKHA6, PLEKHH2, PLXNC1, PMS1, PODN, POLN, POLR1A, POSTN, PPM1E, PPP3CA, PRKCA, PRKDC, PRKG1, PRPH2, PRRG4, PRUNE2, PSMD6-AS2, PTGIS, PTX3, RAB30, RAB38, RAB44, RAD9B, RARS, RBBP8, RBKS, RCC1, RDX, RFWD2, RFX3-AS1, RGCC, RNFT1, ROR1, ROR2, RWDD4, SCARNA9, SCO1, SEC22A, SHROOM3, SIGLEC10, SLC24A3, SLC35F3, SLC39A10, SLC46A2, SLC4A11, SLC6A15, SLC7A11, SLC9A3, SLIT3, SMG1P3, SMTN, SMYD3, SNED1, SORBS2, SORCS2, SOX7, SPDYA, SPEF2, SQRDL, STAC2, STAT1, STAT4, STEAP2, STK32B, STRN4, STS, STXBP6, SULF1, SVEP1, SYNGR2, SYNPO, SYNPO2, SYNPO2L, TAGLN3, TANGO6, TARBP1, TEX21P, TGFA, TGFB2, TGFB3, TGM2, THADA, THBS2, THRB, TMEM102, TMEM119, TMEM256-PLSCR3, TMEM50B, TNC, TNFAIP8L3, TNFRSF14, TNRC18P1, TNS3, TNXB, TP53AIP1, TPRG1, TRAF3, TRIM66, TRPC4, TSHZ2, TSPAN11, TSPAN18, TSPAN7, TSSK3, TXNIP, UNC5B, USP27X, UVRAG, VIM-AS1, VPS41, VSTM2L, VWA8, VWF, WDR91, WISP1, WNT10B, XRN2, YDJC, ZBTB26, ZCCHC5, ZFP82, ZMIZ1-AS1, ZNF212, ZNF350, ZNF660, ZNF79 and ZNF837.
(317) In another specific aspect of the foregoing, the gene is selected from ABCA10, ACTA2, ADAL, ADAMTS1, ADAMTS5, ADD1, ADGRG6, ADH6, ADHFE1, AFF3, AKAP3, ANK1, ANK3, ANKRD33B, AP4B1-AS1, ARHGEF16, ARID5B, ARL9, ASIC1, ATP2A3, B3GALT2, B3GNT6, BCL2L15, BCYRN1, BIN3-IT1, BIRC3, BTG2, C10orf54, C11orf70, C11orf94, C12orf56, C19orf47, C3, C7orf31, C8orf34, CA13, CA3, CACNA2D2, CACNB1, CADM1, CAND2, CCDC79, CCER2, CCNF, CELSR1, CEMIP, CEP170, CFH, CIITA, CLDN23, CMAHP, CNGA4, CNTD1, COL11A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A6, COL8A1, COLEC12, COMP, CPA4, CPQ, CRISPLD2, CRLF1, CRYL1, CYB5R2, CYGB, CYP1B1, DCLK1, DCN, DDIT4L, DDX50, DEGS1, DEPTOR, DFNB59, DIRAS3, DLG5, DNAH8, DNAJC27, DOCK11, DYNC1I1, DZIP1L, EFEMP1, EGR3, ELN, ELP4, EMX2OS, ENPP1, ERCC8, ESM1, EVC2, F2R, FAM160A1, FAM20A, FAM46B, FAM65B, FAP, FARP1, FBLN2, FBN2, FBXO9, FCHO1, FGFR2, FGL2, FLT1, FRAS1, FSCN2, GAL3ST4, GALNT15, GATA6, GBGT1, GCNT1, GDF6, GNAQ, GPR183, GPR50, GPRC5A, GPRC5B, GRTP1, GUCA1B, GXYLT1, HAPLN1, HAPLN2, HAS3, HAVCR2, HDAC5, HECTD2-AS1, HEPH, HEY1, HMGN3-AS1, HOOK3, HSPA1L, HTATIP2, IGDCC4, IGF2R, IGFBP3, IL16, INA, INTU, IQCG, ITGA11, ITGA8, ITGB8, ITIH1, ITPKA, KCNS1, KCNS2, KDM6A, KDSR, KIAA1456, KIAA1462, KIAA1755, KIT, KLF17, KLRG1, KRT7, KRTAP1-1, KRTAP1-5, L3MBTL2, LAMB2P1, LGI2, LGR4, LHX9, LINC00472, LINC00570, LINC00578, LINC00607, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LMOD1, LRBA, LRP4, LRRC32, LRRC39, LSAMP, LUM, LYPD1, MAFB, MAMDC2, MAN2A1, MAPK13, MASP1, MB, MC4R, MEGF6, MIAT, MIR612, MLLT10, MMP10, MMP24, MN1, MOXD1, MRVI1, MSH4, MTERF3, MXRA5, NA, NAALADL2, NAE1, NAGS, NDNF, NGFR, NHLH1, NLN, NOTCH3, NOTUM, NOVA2, NOX4, NRROS, OCLN, OLR1, OSBPL10, OXCT2, PAIP2B, PBLD, PDE1C, PDE5A, PDGFD, PDGFRB, PDS5B, PEAR1, PHACTR3, PI4K2B, PIK3R1, PIM2, PITPNM3, PLEK2, PLEKHA6, PLEKHH2, PODN, POLN, POLR1A, PPM1E, PPP3CA, PRKCA, PRKG1, PRPH2, PRRG4, PRUNE2, PSMD6-AS2, PTGIS, PTX3, RAB30, RAB38, RAB44, RAD9B, RARS, RBBP8, RBKS, RDX, RFX3-AS1, RGCC, ROR1, ROR2, SCARNA9, SHROOM3, SIGLEC10, SLC24A3, SLC35F3, SLC39A10, SLC46A2, SLC4A11, SLC6A15, SLC7A11, SLC9A3, SLIT3, SMG1P3, SMTN, SNED1, SORBS2, SORCS2, SOX7, SPDYA, SPEF2, STAC2, STAT4, STK32B, STRN4, STS, STXBP6, SULF1, SVEP1, SYNGR2, SYNPO, SYNPO2, SYNPO2L, TAGLN3, TANGO6, TEX21P, TGFA, TGFB2, TGFB3, TGM2, THBS2, TMEM102, TMEM119, TMEM256-PLSCR3, TMEM50B, TNFAIP8L3, TNFRSF14, TNRC18P1, TNXB, TP53AIP1, TPRG1, TRIM66, TRPC4, TSHZ2, TSPAN11, TSPAN18, TSPAN7, TSSK3, TXNIP, USP27X, UVRAG, VIM-AS1, VPS41, VSTM2L, VWF, WDR91, WISP1, WNT10B, YDJC, ZBTB26, ZCCHC5, ZFP82, ZMIZ1-AS1, ZNF212, ZNF350, ZNF660, ZNF79 and ZNF837.
(318) In another specific aspect of the foregoing, the gene is selected from ABCB8, ABCC3, ADAM17, ADCY3, AGPAT4, ANKRA2, ANXA11, APIP, APLP2, ARHGAP1, ARL15, ASAP1, ASPH, ATAD2B, ATXN1, AXIN1, BECN1, BHMT2, BICD1, BTN3A1, C11orf30, C11orf73, C12orf4, C14orf32, C8orf44, C8orf44-SGK3, C8orf88, CASC3, CASP7, CCDC122, CDH13, CECR7, CENPI, CEP112, CEP192, CHEK1, CMAHP, CNRIP1, COPS7B, CPSF4, CRISPLD2, CRYBG3, CSNK1E, CSNK1G1, DAGLB, DCAF17, DCUN1D4, DDX42, DENND1A, DENND5A, DGKA, DHFR, DIAPH3, DLGAP4, DNAJC13, DNMBP, DOCK1, DYRK1A, EIF2B3, ENAH, ENOX1, EP300, ERC1, ERCC1, ERGIC3, ERLIN2, ERRFI1, EVC, FAF1, FAIM, FAM126A, FAM13A, FAM162A, FAM174A, FAM198B, FBN2, FER, FHOD3, FOCAD, GALC, GCFC2, GGACT, GGCT, GLCE, GOLGA4, GOLGB1, GPSM2, GULP1, GXYLT1, HAT1, HDX, HLTF, HMGA2, HNMT, HPS1, HSD17B12, HSD17B4, HTT, IFT57, INPP5K, IVD, KDM6A, KIAA1524, KIAA1715, LETM2, LOC400927, LRRC42, LUC7L3, LYRM1, MADD, MB21D2, MCM10, MED13L, MEDAG, MEMO1, MFN2, MMS19, MRPL45, MRPS28, MTERF3, MYCBP2, MYLK, MYOF, NGF, NREP, NSUN4, NT5C2, OSMR, OXCT1, PAPD4, PCM1, PDE7A, PDS5B, PDXDC1, PIGN, PIK3CD, PIK3R1, PIKFYVE, PITPNB, PLEKHA1, PLSCR1, PMS1, POMT2, PPARG, PPHLN1, PPIP5K2, PPP1R26, PRPF31, PRSS23, PRUNE2, PSMA4, PXK, RAF1, RAP1A, RAPGEF1, RARS2, RBKS, RERE, RFWD2, RNFT1, RPA1, RPS10, RPS6KB2, SAMD4A, SAR1A, SCO1, SEC24A, SENP6, SERGEF, SGK3, SH3YL1, SKA2, SLC12A2, SLC25A17, SLC44A2, SMYD3, SNAP23, SNHG16, SNX7, SOS2, SPATA8, SPATA5, SPIDR, SPRYD7, SRGAP1, SRRM1, STAT1, STRN3, STXBP6, SUPT20H, TAF2, TASP1, TBC1D15, TCF12, TCF4, TIAM1, TJP2, TMC3, TMEM189-UBE2V1, TMEM214, TNRC6A, TNS3, TOE1, TRAF3, TRIM65, TSPAN2, TTC7B, TUBE1, TYW5, UBAP2L, UBE2V1, URGCP, VAV2, VPS29, WDR27, WDR37, WDR91, WNK1, XRN2, ZCCHC8, ZFP82, ZNF138, ZNF232, ZNF37BP and ZNF680.
(319) In another specific aspect of the foregoing, the gene is selected from ABCB8, ABCC3, ADCY3, AGPAT4, ANKRA2, APIP, ARHGAP1, ARL15, ATXN1, BECN1, BHMT2, BTN3A, C12orf4, C14orf132, C8orf44, C8orf44-SGK3, C8orf88, CASP7, CCDC122, CECR7, CENPI, CEP112, CEP192, CHEK1, CMAHP, CNRIP1, CPSF4, CRISPLD2, CRYBG3, CSNK1E, CSNK1G1, DAGLB, DCAF17, DLGAP4, DNAJC13, DNMBP, DYRK1A, ENAH, EP300, ERCC1, ERLIN2, ERRFI1, EVC, FAIM, FAM126A, FAM13A, FAM162A, FAM174A, FBN2, GGACT, GLCE, GULP1, GXYLT1, HDX, HMGA2, HNMT, HPS1, IFT57, INPP5K, IVD, KDM6A, LETM2, LOC400927, LRRC42, LYRM1, MB21D2, MCM10, MED13L, MFN2, MRPL45, MRPS28, MTERF3, MYCBP2, NGF, OXCT1, PDS5B, PIGN, PIK3CD, PIK3R1, PIKFYVE, PLEKHA1, PLSCR1, POMT2, PPARG, PPIP5K2, PPP1R26, PRPF31, PRUNE2, PXK, RAF1, RAPGEF1, RARS2, RBKS, RERE, RPA1, RPS10, RPS6KB2, SAMD4A, SEC24A, SENP6, SERGEF, SGK3, SH3YL1, SKA2, SLC12A2, SLC44A2, SNX7, SPATA18, SPATA5, SPIDR, SPRYD7, SRGAP1, SRRM1, STXBP6, TASP1, TCF12, TCF4, TIAM1, TMC3, TMEM189-UBE2V1, TMEM214, TNRC6A, TTC7B, TUBE1, TYW5, URGCP, VAV2, WDR27, WDR91, WNK1, ZCCHC8, ZFP82, ZNF138, ZNF232 and ZNF680.
(320) In another specific aspect of the foregoing, the gene is selected from ABHD10 ADAL, ADAM17, ADAM23, ADAMTS19, AGPAT4, AGPS, AKAP8L, AKT1, ANKRD13C, ANXA11, APIP, APPL2, ARHGAP1, ARHGAP5, ARL15, ARL5B, ARSJ, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BTBD10, C1QTNF9B-AS1, C1orf27, C11orf30, C11orf73, C11orf76, C12orf4, C2orf47, CACNB1, CACNB4, CADM2, CCNL2, CDH18, CENPI, CEP162, CEP170, CEP192, CEP57, CHEK1, CHRM2, CMAHP, CMSS1, CNOT7, CNRIP1, CNTN1, COPS7B, CRISPLD2, CRYBG3, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DENND1A, DENND4A, DENND5A, DET1, DGK1, DHFR, DIAPH3, DLG5, DMXL1, DNAJA4, DNMBP, DYRK1A, DZIP1L, ELMO2, ENAH, ENOX1, EP300, ERC1, ERC2, EVC, EXOC3, EXOC6B, FAM162A, FAM174A, FAM195B, FAM208B, FAM49B, FAM69B, FBN2, FBXL16, FBXO9, FGD4, FHOD3, GALC, GBP1, GLCE, GNG12, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HMGXB4, HOXB3, HSD17B4, HTT, IFT57, IKBKAP, INO80, IPP4B, INVS, ITCH, IVD, KDM6A, KDSR, KIAA1524, KIAA1715, KIDINS220, KIF21A, L3MBTL2, LGALS3, LINCR-0002, LINGO2, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MANEA, MAPK10, MARCH7, MARCH8, MDN1, MEAF6 MEMO1, MFN2, MLLT10, MMS19, MORF4L1, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, MYLK, NEDD4, NFASC, NGF, NIPA1, NLGN1, NLN, NREP, NSUN4, NUPL1, OSBPL3, PAPD4, PBX3, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PIGN, PITPNB, PMS1, PNISR, POMT2, PPARG, PPFIBP1, PRPF31, PSMA4, PXK, RAB23, RAF1, RAPGEF1, RASIP1, RBBP8, RCOR3, RERE, RGL1, RNF130, RNF144A, RNF213, RPF2, RPS10, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SGMS1, SGPL1, SH2B3, SKP1, SLC12A2, SLC25A16, SLC25A17, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA2, SORCS1, SPIDR, SPRYD7, SREK1, SSBP1, STRAD8, STXBP4, STXBP6, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TBL1XR1, TCF4, TEKT4P2, TET1, TIAM1, TJAP1, TJP2, TMEM214, TMX3, TNRC6A, TRAF3, TRIM65, TSPAN7, TXNL4B, UBE2D3, UBE2L3, UBN2, UNC3B, URGCP-MRPS24, UVRAG, VDAC2, WDR27, WDR90, WHSC2, WNK1, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF350, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF777, ZNF7804A, ZNF836 and ZSCAN25.
(321) In another specific aspect of the foregoing, the gene is selected from APOA2, ASAP1, BRCA1, BRCA2, CDKN1C, CRX, CTRC, DENND5A, DIAPH3, DMD, DNAH11, EIF2B3, GALC, HPS1, HTT, IKBKAP, KIAA1524, LMNA, MECP2, PAPD4, PAX6, PCCB, PITPNB, PTCH1, SLC34A3, SMN2, SPINK5, SREK1, TMEM67, VWF, XDH and XRN2.
(322) In another specific aspect of the foregoing, the gene is selected from ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM15, ADAM17, ADAM23, ADAM33, ADAMTS1, ADAMTS19, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP8L, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD13C, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APOA2, APP, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGAP5, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARL5B, ARMCX3, ARSJ, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF6, ATF7IP, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3, BIN3-IT1, BIRC3, BIRC6, BNC1, BNC2, BRCA1, BRCA2, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1QTNF9B-AS1, C1orf27, C1orf86, C10orf54, C11orf30, C11orf70, C11orf73, C11orf76, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C2orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CACNB4, CADM1, CADM2, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCNL2, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDH18, CDK11B, CDK16, CDKAL1, CDKN1C, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP162, CEP170, CEP192, CEP68, CFH, CFLAR, CHD8, CHEK1, CHRM2, CIITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, CMSS1, CNOT7, CNRIP1, CNTN1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRX, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CTRC, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAAM1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND4A, DENND5A, DEPTOR, DET1, DFNB59, DGCR2, DGK1, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DMD, DMXL1, DNAH8, DNAH11, DNAJA4, DNAJC13, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEF1A1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELMO2, ELN, ELP4, EMX2OS, ENAH, ENG, ENOX1, ENPP1, ENPP2, ENSA, EP300, EPT1, ERC1, ERC2, ERCC1, ERCC8, ERLIN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXOC3, EXOC6B, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM195B, FAM198B, FAM20A, FAM208B, FAM219A, FAM219B, FAM3C, FAM46B, FAM49B, FAM65A, FAM65B, FAM69B, FAP, FARP1, FBLN2, FBN2, FBXL16, FBXL6, FBXO9, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD4, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GBP1, GCFC2, GLCE, GCNT1, GDF6, GGACT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNG12, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GTSF1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HMGXB4, HOOK3, HOXB3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IKBKAP, IL16, IL6ST, INA, INHBA, INO80, IPP4B, INPP5K, INSIG1, INTU, INVS, IQCE, IQCG, ITCH, ITGAI1, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIDINS220, KIF14, KIF2A, KIF21A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LATS2, LDLR, LEMD3, LETM2, LGALS3, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, LINC00578, LINC00607, LINC00657, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LINCR-0002, LINGO2, LMAN2L, LMNA, LMO7, LMOD1, LOC400927, LONP1, LOX, LPHN1, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC1, LRRC32, LRRC39, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MACROD2, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MANEA, MAP4K4, MAPK10, MAPK13, MARCH7, MARCH8, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MDN1, MEAF6, MECP2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MORF4L1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR3, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYB, MYCBP2, MYLK, MYO1D, MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NEDD4, NELFA, NEO1, NEURL1B, NF2, NFASC, NFE2L1, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLGN1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL3, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PAX6, PBLD, PBX3, PCBP2, PCCB, PCDH10, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE3A, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PDXDC2P, PEAR1, PELI1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPFIBP1, PPIP5K1, PPIP5K2, PPM1E, PPP1R12A, PPP1R26, PPP3CA, PPP6R1, PPP6R2, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTCH1, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASIP1, RASSF8, RBBP8, RBCK1, RCOR3, RBFOX2, RBKS, RBM10, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGL1, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF130, RNF144A, RNF213, RNF38, RNFT1, ROR1, ROR2, RPA1, RPF2, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A1, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SF3B3, SGIP1, SGK3, SGMS1, SGOL2, SGPL1, SH2B3, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SKP1, SLC12A2, SLC24A3, SLC25A16, SLC25A17, SLC34A3, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMOX, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SNX24, SNX7, SOCS2, SOCS6, SOGA2, SON, SORBS2, SORCS1, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPINK5, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SRGAP1, SRRM1, SRSF3, SSBP1, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRAD8, STRIP1, STRN4, STS, STX16, STXBP4, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBCA, TBL1XR1, TBL2, TCF12, TCF4, TCF7L2, TEKT4P2, TENC1, TENM2, TEP1, TET1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFB1, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJAP1, TJP2, TLE3, TLK1, TMC3, TMEM67, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TMX3, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNL4B, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2D3, UBE2G2, UBE2L3, UBE2V1, UBN2, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC13B, UNC5B, URGCP, URGCP-MRPS24, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VDAC2, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR90, WDR91, WHSC2, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XDH, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMIZ2, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF208, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF280D, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF426, ZNF431, ZNF583, ZNF618, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF730, ZNF74, ZNF764, ZNF777, ZNF778, ZNF780A, ZNF7804A, ZNF79, ZNF827, ZNF836, ZNF837, ZNF839, ZNF91 and ZSCAN25.
(323) In another aspect, the gene is not SMN2.
(324) In another aspect, the gene is not selected from ABHD10, ADAM12, AKT1, ANXA11, APLP2, APPL2, ARMCX6, ATG5, AXIN1, BAIAP2, CCNB1IP1, CCT7, CEP57, CSF1, DLGAP4, EPN1, ERGIC3, FOXM1, GGCT, GRAMD3, HSD17B4, LARP7, LRRC42, MADD, MAN1B1, MRPL39, PCBP4, PPHLN1, PRKACB, RAB23, RAP1A, RCC1, SREK1, STRN3 and TNRC6A.
(325) In another aspect, the gene is not selected from ABHD10, ADAM12, AKT1, ANXA11, APLP2, APPL2, ARMCX6, ATG5, AXIN1, BAIAP2, CCNB1IP1, CCT7, CEP57, CSF1, DLGAP4, EPN1, ERGIC3, FOXM1, GGCT, GRAMD3, HSD17B4, LARP7, LRRC42, MADD, MAN1B1, MRPL39, PCBP4, PPHLN1, PRKACB, RAB23, RAP1A, RCC1, SMN2, SREK1, STRN3 and TNRC6A.
(326) In another particular aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene in a subject, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS (for example, an endogenous intronic REMS or a non-endogenous intronic REMS), the methods comprising administering to the subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(327) In another particular aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene in a subject, wherein the precursor RNA transcript transcribed from the gene comprises a non-endogenous intronic REMS, the methods comprising administering to the subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(328) In another aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(329) In another aspect, provided herein are methods for modifying RNA splicing in order to modulate the amount of one, two, three or more RNA transcripts of a gene described herein, comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes described herein.
(330) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a product of a gene (such as an RNA transcript or a protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding a first exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding a second exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first 5′ splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, a nucleotide sequence encoding an iREMS, a nucleotide sequence encoding a second branch point and a nucleotide sequence encoding a second 3′ splice site, wherein the nucleotide sequence encoding the iREMS comprises a DNA sequence GAgtrngn, and wherein r is adenine or guanine and n is any nucleotide, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.
(331) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a product of a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding a first exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding a second exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence of the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding an iREMS, a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site, wherein the nucleotide sequence encoding the iREMS comprises a DNA sequence GAgtrngn, and wherein r is adenine or guanine and n is any nucleotide, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.
(332) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a product of a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence encodes exonic and intronic elements illustrated in
(333) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a product of a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence encodes exonic and intronic elements illustrated in
(334) In another aspect, provided herein is a method for modifying RNA splicing in order to modulate the amount of a product of a gene (such as an RNA transcript or protein) in a subject, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence encodes exonic and intronic elements illustrated in FIG. 1C, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.
(335) In a specific aspect, the gene is a gene described in a table in this disclosure.
(336) In certain aspects, a compound of Formula (I) or a form thereof contacted or cultured with a cell(s), or administered to a subject is a compound described herein.
(337) Table 3 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon or formation of an eExon with a corresponding change in isoform abundance as a result of iExon or eExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.
(338) TABLE-US-00039 TABLE 3 Table 3 ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM12, ADAM15, ADAM17, ADAM23, ADAM33, ADAMTS1, ADAMTS19, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP8L, AKAP9, AKNA, AKT1, ALCAM, ALDH4A1, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD13C, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APLP2, APOA2, APP, APPL2, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGAP5, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARL5B, ARMCX3, ARMCX6, ARSJ, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF6, ATF7IP, ATG5, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, AXIN1, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3, BIN3-IT1, BIRC3, BIRC6, BNC1, BNC2, BRCA1, BRCA2, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1QTNF9B-AS1, C1orf27, C1orf86, C10orf54, C11orf30, C11orf70, C11orf73, C11orf76, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C2orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CACNB4, CADM1, CADM2, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCNL2, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDH18, CDK11B, CDK16, CDKAL1, CDKN1C, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP162, CEP170, CEP192, CEP57, CEP68, CFH, CFLAR, CHD8, CHEK1, CHRM2, CIITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, CMSS1, CNOT7, CNRIP1, CNTN1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRX, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CTRC, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAAM1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND4A, DENND5A, DEPTOR, DET1, DFNB59, DGCR2, DGK1, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DLGAP4, DMD, DMXL1, DNAH8, DNAH11, DNAJA4, DNAJC13, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEF1A1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELMO2, ELN, ELP4, EMX2OS, ENAH, ENG, ENOX1, ENPP1, ENPP2, ENSA, EP300, EPN1, EPT1, ERC1, ERC2, ERCC1, ERCC8, ERGIC3, ERLIN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXOC3, EXOC6B, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM195B, FAM198B, FAM20A, FAM208B, FAM219A, FAM219B, FAM3C, FAM46B, FAM49B, FAM65A, FAM65B, FAM69B, FAP, FARP1, FBLN2, FBN2, FBXL16, FBXL6, FBXO9, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD4, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GBP1, GCFC2, GLCE, GCNT1, GDF6, GGACT, GGCT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNG12, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GTSF1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HMGXB4, HOOK3, HOXB3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSD17B4, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IKBKAP, IL16, IL6ST, INA, INHBA, INO80, IPP4B, INPP5K, INSIG1, INTU, INVS, IQCE, IQCG, ITCH, ITGA11, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIDINS220, KIF14, KIF2A, KIF21A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LARP7, LATS2, LDLR, LEMD3, LETM2, LGALS3, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, LINC00578, LINC00607, LINC00657, LINC00678, LINC00702, L1NC00886, LINC00961, LINC01011, LINC01118, LINC01204, LINCR-0002, LINGO2, LMAN2L, LMNA, LMO7, LMOD1, LOC400927, LONP1, LOX, LPHN1, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC1, LRRC32, LRRC39, LRRC42, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MACROD2, MADD, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MANEA, MAP4K4, MAPK10, MAPK13, MARCH7, MARCH8, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MDN1, MEAF6, MECP2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MORF4L1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL39, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR3, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYB MYCBP2, MYLK, MYO1D MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NEDD4, NELFA, NEO1, NEURL1B, NF2, NFASC, NFE2L1, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLGN1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL3, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PAX6, PBLD, PBX3, PCBP2, PCBP4, PCCB, PCDH10, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE3A, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PDXDC2P, PEAR1, PELI1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPFIBP1, PPHLN1, PPIP5K1, PPIP5K2, PPM1E, PPP1R12A, PPP1R26, PPP3CA, PPP6R1, PPP6R2, PRKACB, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTCH1, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB23, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAP1A, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASIP1, RASSF8, RBBP8, RBCK1, RCOR3, RBFOX2, RBKS, RBM10, RCC1, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGL1, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF130, RNF144A, RNF213, RNF38, RNFT1, ROR1, ROR2, RPA1, RPF2, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A1, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SF3B3, SGIP1, SGK3, SGMS1, SGOL2, SGPL1, SH2B3, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SKP1, SLC12A2, SLC24A3, SLC25A16, SLC25A17, PTCH1, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMN2, SMOX, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SNX24, SNX7, SOCS2, SOCS6, SOGA2, SON, SORBS2, SORCS1, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPINK5, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRGAP1, SRRM1, SRSF3, SSBP1, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRAD8, STRIP1, STRN3, STRN4, STS, STX16, STXBP4, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBCA, TBL1XR1, TBL2, TCF12, TCF4, TCF7L2, TEKT4P2, TENC1, TENM2, TEP1, TET1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFBI, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJAP1, TJP2, TLE3, TLK1, TMC3, TMEM67, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TMX3, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNRC6A, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNL4B, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2D3, UBE2G2, UBE2L3, UBE2V1, UBN2, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC13B, UNC5B, URGCP, URGCP-MRPS24, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VDAC2, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR90, WDR91, WHSC2, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XDH, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMIZ2, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF208, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF280D, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF426, ZNF431, ZNF583, ZNF618, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF730, ZNF74, ZNF764, ZNF777, ZNF778, ZNF780A, ZNF7804A, ZNF79, ZNF827, ZNF836, ZNF837, ZNF839, ZNF91 and ZSCAN25
(339) Table 4 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon or formation of an eExon with a corresponding change in isoform abundance as a result of iExon or eExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.
(340) TABLE-US-00040 TABLE 4 Table 4 ABCA1, ABCB7, ABCC1, ABHD10, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ADAM12, ADAM15, ADAM17, ADAM33, AFF2, AGK, AGPAT3, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK2, ANKFY1, ANKHD1-EIF4EBP3, ANKRD17, ANKS6, ANP32A, ANXA11, ANXA6, AP2B1, APAF1, APLP2, APP, APPL2, APTX, ARHGAP22, ARID1A, ARID2, ARMCX3, ASAP1, ASL, ASNS, ASPH, ATAD2B, ATF7IP, ATG9A, ATMIN, ATP2C1, ATXN3, AURKA, AXIN1, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BEND6, BICD1, BIN1, BNC1, BRD2, BRPF1, BSCL2, BTBD10, BZW1, C11orf30, C11orf73, C17orf76-AS1, C4orf27, C5orf24, C6orf48, C9orf69, CAB39, CALU, CAMKK1, CAPNS1, CASC3, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC88A, CCDC92, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDK11B, CDK16, CDKAL1, CEP68, CFLAR, CHD8, CIZ1, CLIC1, CLK4, CNOT1, COG1, COL12A1, COL1A1, COL6A1, COPS7B, CPEB2, CREB5, CRLS1, CRTAP, CSDE1, CSNK1A1, CTDSP2, CTNND1, CUL2, CUL4A, CUX1, CYB5B, CYBRD1, CYP51A1, DAB2, DACT1, DAKS, DAXX, DCAF10, DCAF11, DCBLD2, DCUN1D4, DDAH1, DDAH2, DDHD2, DDR1, DDX39B, DDX42, DENND1A, DENND1B, DENND5A, DGCR2, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIS3L, DKFZp434M1735, DKK3, DLC1, DNM2, DOCK1, DPP8, DSEL, DST, DSTN, EBF1, EEA1, EEF1A1, EFCAB14, EGR1, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ENG, ENPP2, ENSA, EPN1, EPT1, ERC1, ERGIC3, ETV5, EXO1, EXTL2, EYA3, FADS1, FADS2, FAF1, FAM111A FAM198B, FAM219A, FAM219B, FAM3C, FAM65A, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FDFT1, FDPS, PER, FEZ1, FGD5-AS1, FGFRL1, FHOD3, FLII, FLNB, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FOXM1, FUS, FYN, GABPB1, GALC, GALNT1, GAS7, GBA2, GCFC2, GGCT, GHDC, GIGYF2, GJC1, GMIP, GNA13, GNAS, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR89A, GPSM2, GREM1, GRK6, GSE1, GTF2H2B, HAS2, HAT1, HAUS3, HAUS6, HDAC7, HEG1, HLA-A, HLA-E, HLTF, HMGA1, HMGB1, HMGCR, HMGCS1, HMOX1, HNRNPR, HNRNPUL1, HP1BP3, HRH1, HSD17B12, HSD17B4, HTT, IARS, IDH1, IDI1, IGF2BP2, IL6ST, INHBA, INSIG1, IQCE, ITGAV, ITGB5, ITM2C, ITSN1, KANSL3, KCNK2, KIAA1033, KIAA1143, KIAA1199, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIF14, KIF2A, KIF3A, KLC1, KLC2, KLF6, KLHL7, KRT18, KRT19, KRT34, KRTAP2-3, LAMA2, LAMB1, LARP4, LARP7, LATS2, LDLR, LEMD3, LGALS8, LIMS1, LINC00341, LINC00657, LMAN2L, LMO7, LONP1, LOX, LRCH4, LRIG1, LRP8, LRRC8A, LSS, LTBR, LUC7L2, LZTS2, MADD, MAGED4, MAGED4B, MAN1A2, MAP4K4, MBD1, MBOAT7, MDM2, MED1, MEDAG, MEF2D, MEIS2, MEMO1, MEPCE, MFGE8, MICAL2, MINPP1, MKL1, MKLN1, MKNK2, MLLT4, MLST8, MMAB, MMS19, MMS22L, MPPE1, MPZL1, MRPL3, MSANTD3, MSC, MSH2, MSH6, MSL3, MEMO1, MSRB3, MTAP, MTERFD1, MTHFD1L, MTMR9, MTRR, MUM1, MVD, MVK, MYADM, MYLK, MYOID, MYO9B, MYOF, NAA35, NADK, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NELFA, NEO1, NEURL1B, NF2, NFE2L1, NFX1, NID1, NID2, NIPA1, NKX3-1, NOL10, NOMO3, NPEPPS, NRD1, NREP, NRG1, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, ODF2, OS9, OSBPL6, OSMR, P4HA1, P4HB, PABPC1, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE4A, PDE7A, PDLIM7, PDXDC1, PEPD, PEX5, PFKP, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGU, PIK3C2B, PITPNA, PITPNB, PITPNM1, PLAU, PLEC, PLEKHB2, PLSCR3, PLXNB2, PLXNC1, PMS1, POLE3, POLR3D, POSTN, POU2F1, PPAPDC1A, PPARA, PPHLN1, PPIP5K1, PPP1R12A, PPP6R1, PPP6R2, PRKACB, PRKDC, PRMT1, PRNP, PRSS23, PSMA4, PSMC1, PSMD6, PTK2B, PTPN14, PUF60, PUS7, PVR, PXN, QKI, RAB23, RAB2B, RAB34, RAD1, RAD23B, RALB, RAP1A, RAP1GDS1, RARG, RASSF8, RBCK1, RBFOX2, RBM10, RCC1, RFTN1, RFWD2, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF38, RNFT1, RPL10, RPS6KC1, RRBP1, RWDD4, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24B, SEC61A1, SEPT9, SERPINE2, SF1, SGOL2, SH3RF1, SKIL, SLC25A17, SLC39A3, SLC41A1, SLC4A4, SLC7A6, SLC7A8, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMN2, SMPD4, SMYD3, SMYD5, SNAP23, SNHG16, SNX14, SOCS2, SON, SOS2, SPATA20, SPATS2, SPG20, SPRED2, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SREK1, SRSF3, STARD4, STAT1, STAT3, STAU1, STC2, STEAP2, STRIP1, STRN3, STX16, SUPT20H, SYNE1, SYNE2, SYT15, SYTL2, TACC1, TAF2, TANC2, TARBP1, TARS, TBC1D15, TBL2, TCF7L2, TENC1, TENM2, TEP1, TET3, TFCP2, TGFBI, TGFBR1, TGFBRAP1, THADA, THAP4, THRB, TIMP2, TJP2, TLE3, TLK1, TMEM154, TMEM47, TMEM63A, TNC, TNFAIP3, TNFRSF12A, TNIP1, TNKS1BP1, TNPO3, TNS1, TNS3, TOE1, TOMM40, TOMM5, TOPORS, TP53INP1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRMT1L, TRPS1, TSC2, TSHZ1, TSPAN2, TTC7A, TUBB2C, TUBB3, TXNL1, TXNRD1, U2SURP, UBAP2L, UBE2G2, UBE2V1, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC5B, USP19, USP7, VANGL1, VARS2, VCL, VIPAS39, VPS13A, VPS29, VPS51, VWA8, WDR19, WDR37, WDR48, WIPF1, WNT5B, WSB1, WWTR1, XIAP, XRN2, YAP1, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZHX3, ZMIZ1, ZMYM2, ZNF12, ZNF148, ZNF219, ZNF227, ZNF24, ZNF268, ZNF28, ZNF281, ZNF335, ZNF37A, ZNF37BP, ZNF395, ZNF583, ZNF621, ZNF652, ZNF655, ZNF674, ZNF74, ZNF764, ZNF778, ZNF780A, ZNF827, ZNF839 and ZNF91
(341) Table 5 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon or formation of an eExon with a corresponding change in isoform abundance as a result of iExon or eExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.
(342) TABLE-US-00041 TABLE 5 Table 5 ABCA1, ABCC1, ABL2, ACACA, ACAT2, AFF2, AHRR, AK021888, AK310472, AKAP1, ANK2, ANKHD1-EIF4EBP3, AP2B1, APAF1, APLP2, ARID1A, ARMCX3, ASAP1, ASPH, ATAD2B, ATF7IP, ATG9A, AXIN1, BACE1, BIN1, BNC1, BRPF1, BZW1, C11orf30, C11orf73, C17orf76-AS1, C4orf27, C6orf48, CAB39, CAMKK1, CCDC88A, CCDC92, CDC25B, CDC42BPA, CDCA7, CDH11, CDH13, CEP68, CFLAR, COPS7B, CREB5, CUL2, CUL4A, CUX1, CYP51A1, DCUN1D4, DDR1, DDX39B, DDX42, DENND1A, DENND5A, DGKA, DHCR24, DHCR7, DIAPH1, DIAPH3, DNM2, DOCK1, EFCAB14, EIF2B3, EPN1, EPT1, ERC1, ETV5, FADS1, FADS2, FAF1, FAM198B, FAM219B, FBXO10, FBXO9, FDFT1, FDPS, FER, FEZ1, FHOD3, FLII, FLNB, FNBP1, FOS, FOSB, FOXM1, FYN, GABPB1, GALC, GAS7, GGCT, GJC1, GPSM2, GRK6, HAS2, HAT1, HLTF, HMGA1, HMGB1, HMGCR, HMGCS1, HMOX1, HP1BP3, HSD17B12, HTT, IDI1, INHBA, INSIG1, KANSL3, KIAA1199, KIAA1524, KIAA1715, KIF3A, KLF6, KRT19, KRT34, KRTAP2-3, LAMA2, LARP7, LDLR, LEMD3, LMAN2L, LRCH4, LRP8, LSS, MAGED4, MAGED4B, MAN1A2, MEDAG, MEF2D, MEMO1, MFGE8, MICAL2, MMAB, MMS19, MMS22L, MSL3, MSMO1, MTAP, MTERFD1, MVD, MVK, NASP, NAV2, NEURL1B, NFE2L1, NID1, NPEPPS, NREP, NRG1, NSUN4, NT5C2, NUP153, P4HA1, PABPC1, PAPD4, PCBP2, PCM1, PCSK9, PDXDC1, PEPD, PHF19, PHF8, PHTF2, PIK3C2B, PITPNB, PLEC, PMS1, POU2F1, PPHLN1, PRKDC, PRSS23, PSMC1, PTPN14, PUF60, PVR, RAB23, RAD23B, RAP1A, RASSF8, RBM10, RCC1, RFWD2, RNFT1, RWDD4, SAMD9L, SART3, SCAF4, SCD, SEC22A, SEC61A1, SERPINE2, SF1, SLC25A17, SLC7A6, SLC7A8, SMN2, SMYD3, SMYD5, SNAP23, SNHG16, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, STARD4, STAT1, STAU1, STEAP2, STRN3, SYNE1, TACC1, TAF2, TANC2, TARBP1, TBC1D15, TEP1, TFCP2, TGFBRAP1, THADA, TIMP2, TLK1, TMEM154, TNS3, TOMM5, TRAF3, TRAK1, TRAPPC12, TRIM2, TRIM26, TRIM65, TSPAN2, U2SURP, UBAP2L, UBE2V1, UCHL5, UHRF1BP1L, VANGL1, VARS2, VPS13A, VPS29, VWA8, WSB1, XIAP, XRN2, YPEL5, ZAK, ZC3H18, ZFAND5, ZMIZ1, ZMYM2, ZNF219, ZNF227, ZNF24, ZNF37A, ZNF37BP, ZNF395, ZNF652, ZNF674, ZNF74 and ZNF778
(343) Table 6 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon or formation of an eExon with a corresponding change in isoform abundance as a result of iExon or eExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.
(344) TABLE-US-00042 TABLE 6 Table 6 ABCC1, ACADVL, ADAM15, AGPAT3, AHRR, AJUBA, AKAP1, AKAP9, ALCAM, ALDH4A1, ANKFY1, AP2B1, APLP2, APP, ARID1A, ARID2, ASPH, ATMIN, BASP1, BC033281, BCAR3, C11orf73, C17orf76-AS1, C5orf24, C6orf48, CAB39, CASP8AP2, CAV1, CCAR1, CCT6A, CD276, CD46, CDC25B, CDK16, CEP68, CHD8, CLIC1, COL12A1, CPEB2, CREB5, CRLS1, CRTAP, CTNND1, CUX1, CYBRD1, DACT1, DCAF10, DCAF11, DDHD2, DDX39B, DIAPH3, DKK3, DLC1, DSTN, EBF1, EGR1, EIF4G1, EIF4G3, ENG, ERC1, ETV5, FAM198B, FAM219A, FAM3C, FEZ1, FGD5-AS1, FLII, FN1, FNBP1, FOS, FOSB, FOXK1, FOXM1, FYN, GABPB1, GALC, GALNT1, GBA2, GGCT, GHDC, GMIP, GNA13, GNAS, GNL3L, GOLGA2, GORASP1, GREM1, GSE1, HAUS6, HDAC7, HEG1, HLA-A, HLA-E, HMGA1, HP1BP3, IL6ST, ITGAV, KIAA1549, KIF14, KLC1, KLF6, KLHL7, KRT18, LAMA2, LAMB1, LARP7, LATS2, LGALS8, LIMS1, LINC00341, LONP1, LOX, MDM2, MEPCE, MINPP1, MLLT4, MPPE1, MRPL3, MSH2, MSH6, MSL3, MTMR9, MTRR, MUM1, MYADM, MYLK, NADK, NAV2, NCSTN, NFE2L1, NID1, NIPA1, NPEPPS, NRD1, NUDT4, NUSAP1, P4HB, PABPC1, PAK4, PAPD4, PCNXL2, PDE4A, PDXDC1, PHRF1, PHTF2, PI4K2A, PIK3C2B, PLAU, PLEKHB2, PLSCR3, PLXNB2, POSTN, POU2F1, PPARA, PPP1R12A, PRKACB, PSMD6, PTPN14, PUS7, QKI, RAB34, RAD1, RAD23B, RASSF8, RBCK1, RBFOX2, RFTN1, RNF19A, RNF38, RPS6KC1, RWDD4, SEC14L1, SEC24B, SERPINE2, SF1, SLC39A3, SLC41A1, SLC4A4, SLC7A6, SMARCA4, SMN2, SNHG16, SNX14, SON, SPRED2, STAU1, STEAP2, STRIP1, STRN3, TBL2, TGFB1, TGFBR1, THAP4, TLE3, TMEM47, TNKS1BP1, TOMM40, TOPORS, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM65, TRMT1L, TRPS1, TXNL1, TXNRD1, U2SURP, UBE2G2, UBE2V1, UHMK1, USP7, VPS29, VWA8, WDR19, WDR37, WIPF1, YPEL5, YTHDF3, Z24749, ZBTB10, ZBTB7A, ZFAND5, ZMIZ1, ZNF12, ZNF148, ZNF335, ZNF395, ZNF583, ZNF621, ZNF655, ZNF74 and ZNF780A
(345) Table 7 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon or formation of an eExon with a corresponding change in isoform abundance as a result of iExon or eExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.
(346) TABLE-US-00043 TABLE 7 Table 7 ABCB7, ABHD10, ABLIM3, ACACA, ADAM12, ADAM17, ADAM33, AGK, AGPS, AHCYL2, AHDC1, AHRR, AK021888, AK310472, AKAP1, AKAP9, AKNA, AMPD2, ANKRD17, ANKS6, ANP32A, ANXA11, ANXA6, APLP2, APP, APPL2, APTX, ARHGAP22, ARMCX3, ASAP1, ASNS, ASPH, ATG9A, ATP2C1, AURKA, AXIN1, B4GALT2, BACE1, BASP1, BEND6, BICD1, BIN1, BRD2, BRPF1, BTBD10, C11orf30, C11orf73, C17orf76-AS1, C4orf27, C6orf48, CAB39, CAPNS1, CASC3, CCDC77, CCDC88A, CD46, CDC40, CDC42BPA, CDCA7, CDH13, CDK11B, CEP68, CIZ1, CLK4, CNOT1, COG1, COL12A1, COL1A1, COL6A1, COPS7B, CSDE1, CSNK1A1, CUX1, CYB5B, CYBRD1, DAB2, DARS, DCBLD2, DCUN1D4, DDAH2, DDR1, DDX39B, DDX42, DENND1A, DENND1B, DENND5A, DGKA, DHFR, DHX9, DIAPH1, DIAPH3, DIS3L, DNM2, DOCK1, DPP8, DSEL, EEA1, EFCAB14, EIF2B3, EIF4G1, EIF4G3, ELF2, ENG, ENPP2, EPN1, EXTL2, EYA3, FAF1, FAM198B, FAM3C, FBXO10, FBXO18, FBXO31, FBXO9, FER, FEZ1, FHOD3, FLII, FN1, FNBP1, FOCAD, FOSL1, FOXM1, GABPB1, GALC, GALNT1, GCFC2, GGCT, GIGYF2, GMIP, GNAS, GNL3L, GOLGB1, GPR89A, GPSM2, GREM1, GRK6, GTF2H2B, HAT1, HAUS3, HEG1, HLA-A, HLTF, HP1BP3, HRH1, HSD17B12, HSD17B4, HTT, IARS, IDH1, IGF2BP2, ITM2C, KCNK2, KIAA1033, KIAA1143, KIAA1522, KIAA1524, KIAA1715, KIF3A, KLHL7, LAMA2, LARP4, LARP7, LATS2, LIMS1, LINC00341, LINC00657, LMAN2L, LMO7, LRCH4, LRIG1, LRRC8A, LTBR, LUC7L2, LZTS2, MADD, MAGED4B, MAN1A2, MAP4K4, MED1, MEDAG, MEF2D, MEIS2, MEMO1, MICAL2, MKLN1, MLLT4, MMS19, MPZL1, MSANTD3, MSC, MSL3, MTAP, MTERFD1, MTHFD1L, MYADM, MYLK, MYO9B, MYOF, NASP, NAV2, NCOA3, NCOA4, NELFA, NEO1, NEURL1B, NF2, NID2, NOL10, NPEPPS, NRG1, NSUN4, NT5C2, NT5E, NTNG1, NUP153, NUP35, NUP50, NUSAP1, ODF2, OS9, OSBPL6, P4HA1, P4HB, PABPC1, PAPD4, PARN, PARP4, PCBP2, PCBP4, PCDHGB3, PCGF3, PCM1, PCMTD2, PDE7A, PDXDC1, PEPD, PFKP, PHF19, PHRF1, PHTF2, PIEZO1, PIGU, PITPNA, PITPNB, PITPNM1, PLAU, PLSCR3, PLXNC1, PMS1, POU2F1, PPAPDC1A, PPHLN1, PPIP5K1, PPP1R12A, PRKDC, PRMT1, PRSS23, PSMA4, PTK2B, PUF60, PVR, RAB23, RAB2B, RAD1, RAD23B, RAP1A, RAP1GDS1, RARG, RASSF8, RBCK1, RCC1, RFWD2, RGS3, RNF14, RNFT1, RPL10, RRBP1, RWDD4, SAR1A, SCAF4, SCAF8, SCLT1, SCO1, SDCBP, SEC22A, SEPT9, SF1, SGOL2, SLC25A17, SLC4A4, SLC7A6, SMARCC2, SMC4, SMC6, SMCHD1, SMN2, SMPD4, SMYD3, SNAP23, SNHG16, SOCS2, SOS2, SPATA20, SPATS2, SPG20, SQRDL, SREBF1, SREK1, SRSF3, STAT1, STAU1, STEAP2, STRN3, STX16, SUPT20H, SYNE1, SYNE2, SYT15, SYTL2, TAF2, TARBP1, TARS, TBL2, TCF7L2, TENC1, TENM2, TEP1, TET3, TGFBR1, THADA, THRB, TJP2, TLE3, TMEM47, TMEM63A, TNFAIP3, TNIP1, TNPO3, TNS1, TNS3, TOE1, TOMM5, TP53INP1, TRAF3, TRAPPC12, TRIM2, TRIM23, TRIM65, TSC2, TSPAN2, TUBB2C, TXNRD1, UBAP2L, UBE2V1, UCHL5, USP19, VANGL1, VIPAS39, VPS29, VPS51, VWA8, WDR48, WNT5B, WSB1, WWTR1, XRN2, YAP1, YES1, YPEL5, YTHDF3, Z24749, ZBTB24, ZC3H14, ZFAND1, ZFAND5, ZHX3, ZMIZ1, ZMYM2, ZNF219, ZNF268, ZNF395, ZNF827 and ZNF91
(347) Table 8 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon or formation of an eExon with a corresponding change in isoform abundance as a result of iExon or eExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.
(348) TABLE-US-00044 TABLE 8 Table 8 ACACA, ACADVL, AFF2, AHCYL2, AHRR, AKAP1, ALDH4A1, ANKRD17, AP2B1, APLP2, ASL, ASPH, ATG9A, ATMIN, ATXN3, BAG2, BASP1, BRPF1, BSCL2, C11orf30, C11orf73, C17orf76-AS1, C6orf48, C9orf69, CAB39, CALU, CDC25B, CDC42BPA, CDKAL1, CLIC1, COL12A1, COL1A1, COL6A1, CSNK1A1, CTDSP2, CUL2, CUL4A, DAXX, DCAF10, DDAH1, DDR1, DDX39B, DENND1A, DGCR2, DKFZp434M1735, DKK3, DNM2, DST, EEF1A1, EFCAB14, EHMT2, EIF4G1, EIF4G2, EIF4G3, ENSA, EXO1, FAM111A, FAM198B, FAM65A, FBXO34, FEZ1, FGD5-AS1, FGFRL1, FLII, FN1, FOXK1, FOXM1, FUS, GALC, GALNT1, GAS7, GCFC2, GGCT, GJC1, GNA13, GNL3L, GOLGA4, GPR1, GREM1, HEG1, HLA-A, HLA-E, HLTF, HNRNPR, HNRNPUL1, IQCE, ITGB5, ITSN1, KIAA1033, KIF2A, KIF3A, KLC2, LATS2, LIMS1, LINC00341, LINC00657, LONP1, LOX, LUC7L2, MBD1, MBOAT7, MEF2D, MEIS2, MICAL2, MKL1, MKNK2, MLST8, MPPE1, MSL3, MSRB3, MTRR, MYADM, MYLK, MYO1D, NAA35, NAV1, NAV2, NCOA1, NFX1, NKX3-1, NOMO3, NRG1, NUDT4, NUPL1, NUSAP1, OSMR, P4HA1, P4HB, PAPD4, PARD3, PARN, PARP14, PARVB, PCBP2, PCBP4, PCGF3, PDLIM7, PDXDC1, PEX5, PFKP, PHRF1, PI4K2A, POLE3, POLR3D, POSTN, PPARA, PPP6R1, PPP6R2, PRNP, PXN, RAB34, RAD23B, RALB, RAP1A, RASSF8, RBCK1, RBFOX2, RGS10, RIF1, RNF14, RNF19A, SAMD9, SCAF4, SDCBP, SERPINE2, SF1, SH3RF1, SKIL, SLC25A17, SLC4A4, SMG1, SMN2, SNHG16, SREBF1, STATS, STC2, STEAP2, STRN3, SYNE1, SYNE2, TACC1, TARS, TGFBI, TMEM47, TNC, TNFRSF12A, TNS1, TRAF3, TRIM28, TSC2, TSHZ1, TTC7A, TUBB2C, TUBBS, TXNL1, TXNRD1, UBE2G2, UBE2V1, UBQLN4, UNC5B, USP19, VARS2, VCL, VPS29, WDR37, WIPF1, WWTR1, ZC3H12C, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZMIZ1, ZNF28, ZNF281, ZNF655, ZNF764 and ZNF839
(349) Table 9 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon or formation of an eExon with a corresponding change in isoform abundance as a result of iExon or eExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.
(350) TABLE-US-00045 TABLE 9 Table 9 ABCB8, ABCC3, ADAM17, ADCY3, AGPAT4, ANKRA2, ANXA11, APIP, APLP2, ARHGAP1, ARL15, ASAP1, ASPH, ATAD2B, ATXN1, AXIN1, BECN1, BHMT2, BICD1, BTN3A1, C11orf30, C11orf73, C12orf4, C14orf132, C8orf44, C8orf44-SGK3, C8orf88, CASC3, CASP7, CCDC122, CDH13, CECR7, CENPI, CEP112, CEP192, CHEK1, CMAHP, CNRIP1, COPS7B, CPSF4, CRISPLD2, CRYBG3, CSNK1E, CSNK1G1, DAGLB, DCAF17, DCUN1D4, DDX42, DENND1A, DENND5A, DGKA, DHFR, DIAPH3, DLGAP4, DNAJC13, DNMBP, DOCK1, DYRK1A, EIF2B3, ENAH, ENOX1, EP300, ERC1, ERCC1, ERGIC3, ERLIN2, ERRFI1, EVC, FAF1, FAIM, FAM126A, FAM13A, FAM162A, FAM174A, FAM198B, FBN2, FER, FHOD3, FOCAD, GALC, GCFC2, GGACT, GGCT, GLCE, GOLGA4, GOLGB1, GPSM2, GULP1, GXYLT1, HAT1, HDX, HLTF, HMGA2, HNMT, HPS1, HSD17B12, HSD17B4, HTT, IFT57, INPP5K, IVD, KDM6A, KIAA1524, KIAA1715, LETM2, LOC400927, LRRC42, LUC7L3, LYRM1, MADD, MB21D2, MCM10, MED13L, MEDAG, MEMO1, MFN2, MMS19, MRPL45, MRPS28, MTERF3, MYCBP2, MYLK, MYOF, NGF, NREP, NSUN4, NT5C2, OSMR, OXCT1, PAPD4, PCM1, PDE7A, PDS5B, PDXDC1, PIGN, PIK3CD, PIK3R1, PIKFYVE, PITPNB, PLEKHA1, PLSCR1, PMS1, POMT2, PPARG, PPHLN1, PPIP5K2, PPP1R26, PRPF31, PRSS23, PRUNE2, PSMA4, PXK, RAFI, RAP1A, RAPGEF1, RARS2, RBKS, RERE, RFWD2, RNFT1, RPA1, RPS10, RPS6KB2, SAMD4A, SAR1A, SCO1, SEC24A, SENP6, SERGEF, SGK3, SH3YL1, SKA2, SLC12A2, SLC25A17, SLC44A2, SMYD3, SNAP23, SNHG16, SNX7, SOS2, SPATA18, SPATA5, SPIDR, SPRYD7, SRGAP1, SRRM1, STAT1, STRN3, STXBP6, SUPT20H, TAF2, TASP1, TBC1D15, TCF12, TCF4, TIAM1, TJP2, TMC3, TMEM189-UBE2V1, TMEM214, TNRC6A, TNS3, TOE1, TRAF3, TRIM65, TSPAN2, TTC7B, TUBE1, TYW5, UBAP2L, UBE2V1, URGCP, VAV2, VPS29, WDR27, WDR37, WDR91, WNK1, XRN2, ZCCHC8, ZFP82, ZNF138, ZNF232, ZNF37BP and ZNF680
(351) Table 10 shows genes that demonstrate an effect on inclusion of an iExon or formation of an eExon with a corresponding change in isoform abundance as a result of iExon or eExon generation in RNA having an intronic REMS sequence in cells treated with Compound 64 (24 nm and 100 nm) resulting in a statistically significant adjusted Fisher's Exact Test p value.
(352) TABLE-US-00046 TABLE 10 Table 10 ABHD10, ADAL, ADAM17, ADAM23, ADAMTS19, AGPAT4, AGPS, AKAP8L, AKT1, ANKRD13C, ANXA11, APIP, APOA2, APPL2, ARHGAP1, ARHGAP5, ARL15, ARL5B, ARSJ, ASAP1, ATF6, BECN1, BHMT2, BIN3, BNC2, BRCA1, BRCA2, BTBD10, C1QTNF9B-AS1, C1ORF27, C11ORF30, C11ORF73, C11ORF76, C12ORF4, C2ORF47, CACNB1, CACNB4, CADM2, CCNL2, CDH18, CDKN1C, CENPI, CEP162, CEP170, CEP192, CEP57, CHEK1, CHRM2, CMAHP, CMSS1, CNOT7, CNRIP1, CNTN1, COPS7B, CRISPLD2, CRX, CRYBG3, CTRC, CUX1, DAAM1, DCAF17, DCUN1D4, DDX42, DENND1A, DENND4A, DENND5A, DET1, DGK1, DHFR, DIAPH3, DLG5, DMXL1, DMD, DNAH11, DNAJA4, DNMBP, DYRK1A, DZIP1L, EIF2B3, ELMO2, ENAH, ENOX1, EP300, ERC1, ERC2, EVC, EXOC3, EXOC6B, FAM162A, FAM174A, FAM195B, FAM208B, FAM49B, FAM69B, FBN2, FBXL16, FBXO9, FGD4, FHOD3, GALC, GBP1, GLCE, GNG12, GOLGB1, GTSF1, GXYLT1, HDAC5, HDX, HMGXB4, HOXB3, HPS1,, HSD17B4, HTT, IFT57, IKBKAP, INO80, IPP4B, INVS, ITCH, IVD, KDM6A, KDSR, KIAA1524, KIAA1715, KIDINS220, KIF21A, L3MBTL2, LGALS3, LINCR-0002, LINGO2, LMNA, LOC400927, LPHN1, LRRC1, LRRC42, LYRM1, MACROD2, MANEA, MAPK10, MARCH7, MARCH8, MDN1, MEAF6, MECP2, MEMO1, MFN2, MLLT10, MMS19, MORF4L1, MRPL39, MRPL45, MRPS28, MTMR3, MYB, MYCBP2, MYLK, NEDD4, NFASC, NGF, NIPA1, NLGN1, NLN, NREP, NSUN4, NUPL1, OSBPL3, PAPD4, PAX6, PBX3, PCCB, PCDH10, PDE3A, PDE7A, PDXDC1, PDXDC2P, PELI1, PIGN, PITPNB, PMS1, PNISR, POMT2, PPARG, PPFIBP1, PRPF31, PSMA4, PTCH1, PXK, RAB23, RAF1, RAPGEF1, RASIP1, RBBP8, RCOR3, RERE, RGL1, RNF130, RNF144A, RNF213, RPF2, RPS10, SAMD4A, SCO1, SENP6, SF3B3, SGIP1, SGMS1, SGPL1, SH2B3, SKP1, SLC12A2, SLC25A16, SLC25A17, SLC34A3, SMN2, SMOX, SNAP23, SNX24, SNX7, SOCS6, SOGA2, SORCS1, SPIDR, SPINK5, SPRYD7, SREK1, SSBP1, STRAD8, STXBP4, STXBP6, SUPT20H, TAF2, TARBP1, TASP1, TBCA, TBL1XR1, TCF4, TEKT4P2, TET1, TIAM1, TJAP1, TJP2, TMEM67, TMEM214, TMX3, TNRC6A TRAF3, TRIM65, TSPAN7, TXNL4B, UBE2D3, UBE2L3, UBN2, UNC13B, URGCP-MRPS24, UVRAG, VDAC2, VWF, WDR27, WDR90, WHSC2, WNK1, XDH, XRN2, ZFP82, ZMIZ2, ZNF138, ZNF208, ZNF212, ZNF280D, ZNF350, ZNF37BP, ZNF426, ZNF618, ZNF680, ZNF730, ZNF777, ZNF7804A, ZNF836 and ZSCAN25
(353) Table 11 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon or formation of an eExon with a corresponding change in isoform abundance as a result of iExon or eExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.
(354) TABLE-US-00047 TABLE 11 Table 11 APOA2, ASAP1, BRCA1, BRCA2, CDKN1C, CRX, CTRC, DENND5A, DIAPH3, DMD, DNAH11, EIF2B3, GALC, HPS1, HTT, IKBKAP, KIAA1524, LMNA, MECP2, PAPD4, PAX6, PCCB, PITPNB, PTCH1, SLC34A3, SMN2, SPINK5, SREK1, TMEM67, VWF, XDH and XRN2
(355) Table 12 shows certain genes that are expected to demonstrate an effect on inclusion of an iExon or formation of an eExon with a corresponding change in isoform abundance as a result of iExon or eExon generation in RNA having intronic REMS elements in the presence of a compound as described herein. The change in abundance is expected to have a statistically significant p value.
(356) TABLE-US-00048 TABLE 12 Table 12 ABCA1, ABCA10, ABCB7, ABCB8, ABCC1, ABCC3, ABL2, ABLIM3, ACACA, ACADVL, ACAT2, ACTA2, ADAL, ADAM15, ADAM17, ADAM23, ADAM33, ADAMTS1, ADAMTS19, ADCY3, ADD1, ADGRG6, ADH6, ADHFE1, AFF2, AFF3, AGK, AGPAT3, AGPAT4, AGPS, AHCYL2, AHDC1, AHRR, AJUBA, AK021888, AK310472, AKAP1, AKAP3, AKAP8L, AKAP9, AKNA, ALCAM, ALDH4A1, AMPD2, ANK1, ANK2, ANK3, ANKFY1, ANKHD1-EIF4EBP3, ANKRA2, ANKRD13C, ANKRD17, ANKRD33B, ANKRD36, ANKS6, ANP32A, ANXA6, AP2B1, AP4B1-AS1, APAF1, APIP, APOA2, APP, APTX, ARHGAP1, ARHGAP12, ARHGAP22, ARHGAP5, ARHGEF16, ARID1A, ARID2, ARID5B, ARL9, ARL15, ARL5B, ARMCX3, ARSJ, ASAP1, ASIC1, ASL, ASNS, ASPH, ATAD2B, ATF6, ATF7IP, ATG9A, ATMIN, ATP2A3, ATP2C1, ATXN1, ATXN3, AURKA, B3GALT2, B3GNT6, B4GALT2, BACE1, BAG2, BASP1, BC033281, BCAR3, BCL2L15, BCYRN1, BECN1, BEND6, BHMT2, BICD1, BIN1, BIN3, BIN3-IT1, BIRC3, BIRC6, BNC1, BNC2, BRCA1, BRCA2, BRD2, BRPF1, BSCL2, BTBD10, BTG2, BTN3A1, BZW1, C1QTNF9B-AS1, C1orf27, C1orf86, C10orf54, C11orf30, C11orf70, C11orf73, C11orf76, C11orf94, C12orf4, C12orf56, C14orf132, C17orf76-AS1, C19orf47, C2orf47, C3, C4orf27, C5orf24, C6orf48, C7orf31, C8orf34, C8orf44, C8orf44-SGK3, C8orf88, C9orf69, CA13, CA3, CAB39, CACNA2D2, CACNB1, CACNB4, CADM1, CADM2, CALU, CAMKK1, CAND2, CAPNS1, CASC3, CASP7, CASP8AP2, CAV1, CCAR1, CCDC77, CCDC79, CCDC88A, CCDC92, CCDC122, CCER2, CCNF, CCNL2, CCT6A, CD276, CD46, CDC25B, CDC40, CDC42BPA, CDCA7, CDH11, CDH13, CDH18, CDK11B, CDK16, CDKAL1, CDKN1C, CECR7, CELSR1, CEMIP, CENPI, CEP112, CEP162, CEP170, CEP192, CEP68, CFH, CFLAR, CHD8, CHEK1, CHRM2, CIITA, CIZ1, CLDN23, CLIC1, CLK4, CLTA, CMAHP, CNGA4, CNOT1, CNRIP1, CNTD1, CMSS1, CNOT7, CNRIP1, CNTN1, COG1, COL1A1, COL11A1, COL12A1, COL14A1, COL15A1, COL5A1, COL5A3, COL6A1, COL6A6, COL8A1, COLEC12, COMP, COPS7B, CPA4, CPEB2, CPQ, CPSF4, CREB5, CRISPLD2, CRLF1, CRLS1, CRTAP, CRX, CRYBG3, CRYL1, CSDE1, CSNK1A1, CSNK1E, CSNK1G1, CTDSP2, CTNND1, CTRC, CUL2, CUL4A, CUX1, CYB5B, CYB5R2, CYBRD1, CYGB, CYP1B1, CYP51A1, DAAM1, DAB2, DACT1, DAGLB, DARS, DAXX, DCAF10, DCAF11, DCAF17, DCBLD2, DCLK1, DCN, DCUN1D4, DDAH1, DDAH2, DDHD2, DDIT4L, DDR1, DDX39B, DDX42, DDX50, DEGS1, DENND1A, DENND1B, DENND4A, DENND5A, DEBTOR, DET1, DFNB59, DGCR2, DGK1, DGKA, DHCR24, DHCR7, DHFR, DHX9, DIAPH1, DIAPH3, DIRAS3, DIS3L, DKFZp434M1735, DKK3, DLC1, DLG5, DMD, DMXL1, DNAH8, DNAH11, DNAJA4, DNAJC13, DNAJC27, DNM2, DNMBP, DOCK1, DOCK11, DPP8, DSEL, DST, DSTN, DYNC1I1, DYRK1A, DZIP1L, EBF1, EEA1, EEF1A1, EFCAB14, EFEMP1, EGR1, EGR3, EHMT2, EIF2B3, EIF4G1, EIF4G2, EIF4G3, ELF2, ELMO2, ELN, ELP4, EMX2OS, ENAH, ENG, ENOX1, ENPP1, ENPP2, ENSA, EP300, EPT1, ERC1, ERC2, ERCC1, ERCC8, ERLIN2, ERRFI1, ESM1, ETV5, EVC, EVC2, EXO1, EXOC3, EXOC6B, EXTL2, EYA3, F2R, FADS1, FADS2, FAF1, FAIM, FAM111A, FAM126A, FAM13A, FAM160A1, FAM162A, FAM174A, FAM195B, FAM198B, FAM20A, FAM208B, FAM219A, FAM219B, FAM3C, FAM46B, FAM49B, FAM65A, FAM65B, FAM69B, FAP, FARP1, FBLN2, FBN2, FBXL16, FBXL6, FBXO9, FBXO10, FBXO18, FBXO31, FBXO34, FBXO9, FCHO1, FDFT1, FDPS, FER, FEZ1, FGD4, FGD5-AS1, FGFR2, FGFRL1, FGL2, FHOD3, FLII, FLNB, FLT1, FN1, FNBP1, FOCAD, FOS, FOSB, FOSL1, FOXK1, FRAS1, FSCN2, FUS, FYN, GABPB1, GAL3ST4, GALC, GALNT1, GALNT15, GAS7, GATA6, GBA2, GBGT1, GBP1, GCFC2, GLCE, GCNT1, GDF6, GGACT, GHDC, GIGYF2, GJC1, GLCE, GMIP, GNA13, GNAQ, GNAS, GNG12, GNL3L, GOLGA2, GOLGA4, GOLGB1, GORASP1, GPR1, GPR183, GPR50, GPR89A, GPRC5A, GPRC5B, GPSM2, GREM1, GRK6, GRTP1, GSE1, GTF2H2B, GTSF1, GUCA1B, GULP1, GXYLT1, HAPLN1, HAPLN2, HAS2, HAS3, HAT1, HAUS3, HAUS6, HAVCR2, HDAC5, HDAC7, HDX, HECTD2-AS1, HEG1, HEPH, HEY1, HLA-A, HLA-E, HLTF, HMGA1, HMGA2, HMGB1, HMGCR, HMGN3-AS1, HMGCS1, HMGXB4, HOOK3, HOXB3, HMOX1, HNMT, HNRNPR, HNRNPUL1, HP1BP3, HPS1, HRH1, HSD17B12, HSPA1L, HTATIP2, HTT, IARS, IDH1, IDI1, IFT57, IGDCC4, IGF2BP2, IGF2R, IGFBP3, IKBKAP, IL16, IL6ST, INA, INHBA, INO80, IPP4B, INPP5K, INSIG1, INTU, INVS, IQCE, IQCG, ITCH, ITGA11, ITGA8, ITGAV, ITGB5, ITGB8, ITIH1, ITM2C, ITPKA, ITSN1, IVD, KANSL3, KAT6B, KCNK2, KCNS1, KCNS2, KDM6A, KDSR, KIAA1033, KIAA1143, KIAA1199, KIAA1456, KIAA1462, KIAA1522, KIAA1524, KIAA1549, KIAA1715, KIAA1755, KIDINS220, KIF14, KIF2A, KIF21A, KIF3A, KIT, KLC1, KLC2, KLF17, KLF6, KLHL7, KLRG1, KMT2D, KRT7, KRT18, KRT19, KRT34, KRTAP1-1, KRTAP1-5, KRTAP2-3, L3MBTL2, LAMA2, LAMB1, LAMB2P1, LARP4, LATS2, LDLR, LEMD3, LETM2, LGALS3, LGALS8, LGI2, LGR4, LHX9, LIMS1, LINC00341, LINC00472, LINC00570, LINC00578, LINC00607, LINC00657, LINC00678, LINC00702, LINC00886, LINC00961, LINC01011, LINC01118, LINC01204, LINCR-0002, LINGO2, LMAN2L, LMNA, LMO7, LMOD1, LOC400927, LONP1, LOX, LPHN1, LRBA, LRCH4, LRIG1, LRP4, LRP8, LRRC1, LRRC32, LRRC39, LRRC8A, LSAMP, LSS, LTBR, LUC7L2, LUM, LYPD1, LYRM1, LZTS2, MACROD2, MAFB, MAGED4, MAGED4B, MAMDC2, MAN1A2, MAN2A1, MAN2C1, MANEA, MAP4K4, MAPK10, MAPK13, MARCH7, MARCH8, MASP1, MB, MB21D2, MBD1, MBOAT7, MC4R, MCM10, MDM2, MDN1, MEAF6, MECP2, MED1, MED13L, MEDAG, MEF2D, MEGF6, MEIS2, MEMO1, MEPCE, MFGE8, MFN2, MIAT, MICAL2, MINPP1, MIR612, MKL1, MKLN1, MKNK2, MLLT4, MLLT10, MLST8, MMAB, MMP10, MMP24, MMS19, MMS22L, MN1, MORF4L1, MOXD1, MPPE1, MPZL1, MRPL3, MRPL45, MRPL55, MRPS28, MRVI1, MSANTD3, MSC, MSH2, MSH4, MSH6, MSL3, MSMO1, MSRB3, MTAP, MTERF3, MTERFD1, MTHFD1L, MTMR3, MTMR9, MTRR, MUM1, MVD, MVK, MXRA5, MYADM, MYB, MYCBP2, MYLK, MYO1D, MYO9B, MYOF, NA, NAA35, NAALADL2, NADK, NAE1, NAGS, NASP, NAV1, NAV2, NCOA1, NCOA3, NCOA4, NCSTN, NDNF, NEDD4, NELFA, NEO1, NEURL1B, NF2, NFASC, NFE2L1, NFX1, NGF, NGFR, NHLH1, NID1, NID2, NIPA1, NKX3-1, NLGN1, NLN, NOL10, NOMO3, NOTCH3, NOTUM, NOVA2, NOX4, NPEPPS, NRD1, NREP, NRG1, NRROS, NSUN4, NT5C2, NT5E, NTNG1, NUDT4, NUP153, NUP35, NUP50, NUPL1, NUSAP1, OCLN, ODF2, OLR1, OS9, OSBPL3, OSBPL6, OSBPL10, OSMR, OXCT1, OXCT2, P4HA1, P4HB, PABPC1, PAIP2B, PAK4, PAPD4, PARD3, PARN, PARP14, PARP4, PARVB, PAX6, PBLD, PBX3, PCBP2, PCCB, PCDH10, PCDHGB3, PCGF3, PCM1, PCMTD2, PCNXL2, PCSK9, PDE1C, PDE3A, PDE4A, PDE5A, PDE7A, PDGFD, PDGFRB, PDLIM7, PDS5B, PDXDC1, PDXDC2P, PEAR1, PELI1, PEPD, PEX5, PFKP, PHACTR3, PHF19, PHF8, PHRF1, PHTF2, PI4K2A, PIEZO1, PIGN, PIGU, PIK3C2B, PIK3CD, PIK3R1, PIKFYVE, PIM2, PITPNA, PITPNB, PITPNM1, PITPNM3, PLAU, PLEC, PLEK2, PLEKHA1, PLEKHA6, PLEKHB2, PLEKHH2, PLSCR1, PLSCR3, PLXNB2, PLXNC1, PMS1, PNISR, PODN, POLE3, POLN, POLR1A, POLR3D, POMT2, POSTN, POU2F1, PPAPDC1A, PPARA, PPARG, PPFIBP1, PPIP5K1, PPIP5K2, PPM1E, PPP1R12A, PPP1R26, PPP3CA, PPP6R1, PPP6R2, PRKCA, PRKDC, PRKG1, PRMT1, PRNP, PRPF31, PRPH2, PRRG4, PRSS23, PRUNE2, PSMA4, PSMC1, PSMD6, PSMD6-AS2, PTCH1, PTGIS, PTK2B, PTPN14, PTX3, PUF60, PUS7, PVR, PXK, PXN, QKI, RAB2B, RAB30, RAB34, RAB38, RAB44, RAD1, RAD9B, RAD23B, RAF1, RALB, RAP1GDS1, RAPGEF1, RARG, RARS, RARS2, RASIP1, RASSF8, RBBP8, RBCK1, RCOR3, RBFOX2, RBKS, RBM10, RDX, RERE, RFTN1, RFWD2, RFX3-AS1, RGCC, RGL1, RGS10, RGS3, RIF1, RNF14, RNF19A, RNF130, RNF144A, RNF213, RNF38, RNFT1, ROR1, ROR2, RPA1, RPF2, RPL10, RPS10, RPS6KB2, RPS6KC1, RRBP1, RWDD4, SAMD4A, SAMD9, SAMD9L, SAR1A, SART3, SCAF4, SCAF8, SCARNA9, SCD, SCLT1, SCO1, SDCBP, SEC14L1, SEC22A, SEC24A, SEC24B, SEC61A1, SENP6, SEPT9, SERGEF, SERPINE2, SF1, SF3B3, SGIP1, SGK3, SGMS1, SGOL2, SGPL1, SH2B3, SH3RF1, SH3YL1, SHROOM3, SIGLEC10, SKA2, SKIL, SKP1, SLC12A2, SLC24A3, SLC25A16, SLC25A17, SLC34A3, SLC35F3, SLC39A3, SLC39A10, SLC4A4, SLC4A11, SLC41A1, SLC44A2, SLC46A2, SLC6A15, SLC7A6, SLC7A8, SLC7A11, SLC9A3, SLIT3, SMARCA4, SMARCC2, SMC4, SMC6, SMCHD1, SMG1, SMG1P3, SMOX, SMPD4, SMTN, SMYD3, SMYD5, SNAP23, SNED1, SNHG16, SNX7, SNX14, SNX24, SNX7, SOCS2, SOCS6, SOGA2, SON, SORBS2, SORCS1, SORCS2, SOS2, SOX7, SPATA18, SPATA20, SPATA5, SPATS2, SPDYA, SPEF2, SPG20, SPIDR, SPINK5, SPRED2, SPRYD7, SQLE, SQRDL, SQSTM1, SRCAP, SREBF1, SRGAP1, SRRM1, SRSF3, SSBP1, STAC2, STARD4, STAT1, STAT3, STAT4, STAU1, STC2, STEAP2, STK32B, STRAD8, STRIP1, STRN4, STS, STX16, STXBP4, STXBP6, SULF1, SUPT20H, SVEP1, SYNE1, SYNE2, SYNGR2, SYNPO, SYNPO2, SYNPO2L, SYT15, SYTL2, TACC1, TAF2, TAGLN3, TANC2, TANGO6, TARBP1, TARS, TASP1, TBC1D15, TBCA, TBL1XR1, TBL2, TCF12, TCF4, TCF7L2, TEKT4P2, TENC1, TENM2, TEP1, TET1, TET3, TEX21P, TFCP2, TGFA, TGFB2, TGFB3, TGFBI, TGFBR1, TGFBRAP1, TGM2, THADA, THAP4, THBS2, THRB, TIAM1, TIMP2, TJAP1, TJP2, TLE3, TLK1, TMC3, TMEM67, TMEM102, TMEM119, TMEM134, TMEM154, TMEM189-UBE2V1, TMEM214, TMEM256-PLSCR3, TMEM47, TMEM50B, TMEM63A, TMX3, TNC, TNFAIP3, TNFAIP8L3, TNFRSF12A, TNFRSF14, TNIP1, TNKS1BP1, TNPO3, TNRC18P1, TNS1, TNS3, TNXB, TOE1, TOMM40, TOMM5, TOPORS, TP53AIP1, TP53INP1, TPRG1, TRAF3, TRAK1, TRAPPC12, TRIB1, TRIM2, TRIM23, TRIM26, TRIM28, TRIM65, TRIM66, TRMT1L, TRPC4, TRPS1, TSC2, TSHZ1, TSHZ2, TSPAN11, TSPAN18, TSPAN2, TSPAN7, TSSK3, TTC7A, TTC7B, TUBB2C, TUBB3, TUBE1, TXNIP, TXNL1, TXNL4B, TXNRD1, TYW5, U2SURP, UBAP2L, UBE2D3, UBE2G2, UBE2L3, UBE2V1, UBN2, UBQLN4, UCHL5, UHMK1, UHRF1BP1L, UNC13B, UNC5B, URGCP, URGCP-MRPS24, USP19, USP7, USP27X, UVRAG, VANGL1, VARS2, VAV2, VCL, VDAC2, VIM-AS1, VIPAS39, VPS13A, VPS29, VPS41, VPS51, VSTM2L, VWA8, VWF, WDR19, WDR27, WDR37, WDR48, WDR90, WDR91, WHSC2, WIPF1, WISP1, WNK1, WNT5B, WNT10B, WSB1, WWTR1, XDH, XIAP, XRN2, YAP1, YDJC, YES1, YPEL5, YTHDF3, Z24749, ZAK, ZBTB10, ZBTB24, ZBTB26, ZBTB7A, ZC3H12C, ZC3H14, ZC3H18, ZCCHC5, ZCCHC8, ZCCHC11, ZEB1, ZEB2, ZFAND1, ZFAND5, ZFP82, ZHX3, ZMIZ1, ZMIZ1-AS1, ZMIZ2, ZMYM2, ZNF12, ZNF138, ZNF148, ZNF208, ZNF212, ZNF219, ZNF227, ZNF232, ZNF24, ZNF268, ZNF28, ZNF280D, ZNF281, ZNF335, ZNF350, ZNF37A, ZNF37BP, ZNF395, ZNF426, ZNF431, ZNF583, ZNF618, ZNF621, ZNF652, ZNF655, ZNF660, ZNF674, ZNF680, ZNF730, ZNF74, ZNF764, ZNF777, ZNF778, ZNF780A, ZNF7804A, ZNF79, ZNF827, ZNF836, ZNF837, ZNF839, ZNF91 and ZSCAN25
Methods of Preventing and/or Treating Diseases
(357) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease associated with the aberrant expression of a product of a gene (e.g., an mRNA transcript or protein), wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a 5′ splice site, a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(358) In certain aspects, the gene is any one of the genes described herein. In certain aspects, the gene contains a nucleotide sequence encoding a non-endogenous intronic REMS. In one aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease associated with aberrant expression of a product of a gene (e.g., an mRNA, RNA transcript or protein) described herein, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
(359) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease associated with aberrant expression of a product of a gene described herein (e.g., an mRNA, RNA transcript or protein), wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(360) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease associated with aberrant expression of a product of a gene (e.g., an mRNA, RNA transcript or protein) described herein, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a 5′ splice site, a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(361) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease associated with aberrant expression of a product of a gene described herein (e.g., an mRNA, RNA transcript or protein), comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes described herein.
(362) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease in which a change in the level of expression of one, two, three or more RNA isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a 5′ splice site, a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(363) In certain aspects, the gene is any one of the genes described herein. In certain aspects, the gene contains a nucleotide sequence encoding the non-endogenous intronic REMS. In one aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease in which the modulation (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene described herein is beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
(364) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease in which the modulation (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene described herein is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a 5′ splice site, a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(365) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease in which the modulation (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene described herein is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a 5′ splice site, a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript contains in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript contains in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(366) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease in which the modulation (e.g., increase or decrease) in the expression one, two, three or more RNA isoforms encoded by a gene described herein is beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, one, two, three or more RNA isoforms encoded by a gene described herein are decreased following administration of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes described herein.
(367) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease in which a change in the level of expression of one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a 5′ splice site, a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript comprises in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(368) In certain aspects, the gene is any one of the genes described herein. In certain aspects, the gene contains a nucleotide sequence encoding a non-endogenous intronic REMS. In one aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease in which the modulation (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene described herein is beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
(369) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease in which the modulation (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene described herein is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a 5′ splice site, a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript comprises in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(370) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease in which the modulation (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene described herein is beneficial to the prevention and/or treatment of the disease, wherein the precursor RNA transcript transcribed from the gene comprises an intronic REMS, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a 5′ splice site, a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. In another specific aspect, the precursor RNA transcript comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an intronic REMS, a second branch point, and a second 3′ splice site. In another specific aspect the precursor RNA transcript comprises in 5′ to 3′ order: an intronic REMS, a branch point, and a 3′ splice site.
(371) In another aspect, provided herein are methods for modifying RNA splicing in order to prevent and/or treat a disease in which the modulation (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene described herein is beneficial to the prevention and/or treatment of the disease, the methods comprising administering to a human or non-human subject a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In a specific aspect, one, two, three or more RNA isoforms encoded by a gene described herein are decreased following administration of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. See the example section for additional information regarding the genes described herein.
(372) In another aspect, provided herein is a method for modifying RNA splicing in order to prevent, treat or prevent and treat a disease in a subject in which the modulation (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding a first exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding a second exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first 5′ splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, a nucleotide sequence encoding an iREMS, a nucleotide sequence encoding a second branch point and a nucleotide sequence encoding a second 3′ splice site, wherein the nucleotide sequence encoding the iREMS comprises a DNA sequence GAgtrngn, and wherein r is adenine or guanine and n is any nucleotide, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.
(373) In another aspect, provided herein is a method for modifying RNA splicing in order to prevent, treat or prevent and treat a disease in a subject in which the modulation (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, wherein the nucleotide sequence encoding a first exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding a second exon is downstream of the nucleotide sequence encoding the intron, wherein the DNA nucleotide sequence of the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding an iREMS, a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site, wherein the nucleotide sequence encoding the iREMS comprises a DNA sequence GAgtrngn, and wherein r is adenine or guanine and n is any nucleotide, the method comprising administering a compound described herein (for example, a compound of Formula (I) or a form thereof) to the subject.
(374) In another aspect, provided herein is a method for modifying RNA splicing in order to prevent, treat or prevent and treat a disease in a subject in which the modulation (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence encodes exonic and intronic elements illustrated in
(375) In another aspect, provided herein is a method for modifying RNA splicing in order to prevent, treat or prevent and treat a disease in a subject in which the modulation (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron, and wherein the DNA nucleotide sequence encodes exonic and intronic elements illustrated in
(376) In another aspect, provided herein is a method for modifying RNA splicing in order to prevent, treat or prevent and treat a disease in a subject in which the modulation (e.g., increase or decrease) in the expression one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, wherein the gene comprises a DNA nucleotide sequence encoding two exons and an intron and wherein the DNA nucleotide sequence encodes exonic and intronic elements illustrated in
(377) In a specific aspect, the gene is a gene described in a table in this disclosure.
(378) In some aspects, the compound of Formula (I) or a form thereof that is administered to a subject is a compound described herein.
(379) In a specific aspect, the methods for modifying RNA splicing in order to prevent a disease described herein prevent the onset or development of one or symptoms of the disease. In another aspect, the methods for preventing a disease described herein prevent the recurrence of the disease or delays the recurrence of the disease. In another aspect, the methods for treating a disease described herein has one, two or more of the effects: (i) reduce or ameliorate the severity of the disease; (ii) inhibit the progression of the disease; (iii) reduce hospitalization of a subject; (iv) reduce hospitalization length for a subject: (v) increase the survival of a subject; (vi) improve the quality of life of a subject; (vii) reduce the number of symptoms associated with the disease; (viii) reduce or ameliorates the severity of a symptom(s) associated with the disease; (ix) reduce the duration of a symptom(s) associated with the disease; (x) prevent the recurrence of a symptom associated with the disease; (xi) inhibit the development or onset of a symptom of the disease; and/or (xii) inhibit of the progression of a symptom associated with the disease.
(380) Artificial Gene Constructs
(381) Also provided herein are artificial gene constructs comprising a DNA sequence encoding exons and one or more introns, wherein the nucleotide sequence encoding at least one intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a branch point, a nucleotide sequence encoding a 3′ splice site and a nucleotide sequence encoding an intronic REMS, and artificial gene constructs comprising an RNA sequence that comprises exons and one or more introns, wherein at least one intron comprises in 5′ to 3′ order: a branch point, a 3′ splice site and an intronic REMS. The DNA sequence described herein can be or derived from, for example, a genomic DNA sequence or a DNA analog thereof. The RNA sequence described herein can be or derived from, for example, a precursor RNA transcript or an RNA analog thereof. As used herein, the term “artificial gene construct” refers to a DNA or RNA gene construct that comprises a nucleotide sequence not found in nature.
(382) In another aspect, provided herein is an artificial gene construct comprising an RNA sequence comprising two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the RNA nucleotide sequence of the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an iREMS, a second branch point and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, and wherein r is adenine or guanine and n is any nucleotide.
(383) In another aspect, provide herein is an artificial gene construct comprising an RNA sequence comprising two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the RNA nucleotide sequence of the intron comprises in 5′ to 3′ order: an iREMS, a branch point and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, and wherein r is adenine or guanine and n is any nucleotide.
(384) In another aspect, provided herein is an artificial gene construct comprising an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in
(385) In another aspect, provided herein is an artificial gene construct comprising an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in
(386) In another aspect, provided herein is an artificial gene construct comprising an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in
(387) In another aspect, provided herein is an artificial gene construct comprising a DNA sequence encoding two exons and an intron, wherein the nucleotide sequence encoding a first exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding a second exon is downstream of the nucleotide sequence encoding the intron, wherein the nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first 5′ splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, an iREMS, a nucleotide sequence encoding a second branch point and a nucleotide sequence encoding a second 3′ splice site, wherein the nucleotide sequence encoding the iREMS comprises a DNA sequence GAgtrngn, and wherein r is adenine or guanine and n is any nucleotide.
(388) In another aspect, provide herein is an artificial gene construct comprising a DNA sequence encoding two exons and an intron, wherein the nucleotide sequence encoding a first exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding a second exon is downstream of the nucleotide sequence encoding the intron, wherein the nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding an iREMS, a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site, wherein the nucleotide sequence encoding the iREMS comprises an DNA sequence GAgtrngn, wherein r is adenine or guanine and n is any nucleotide.
(389) In another aspect, provide herein is an artificial gene construct comprising a DNA sequence encoding two exons and an intron, wherein the DNA sequence encodes exonic and intronic elements illustrated in
(390) In another aspect, provide herein is an artificial gene construct comprising a DNA sequence encoding two exons and an intron, wherein the DNA sequence encodes exonic and intronic elements illustrated in
(391) In another aspect, provide herein is an artificial gene construct comprising a DNA sequence encoding two exons and an intron, wherein the DNA sequence encodes exonic and intronic elements illustrated in
(392) In one aspect, provided herein are artificial gene constructs comprising an intronic REMS. In one aspect, an artificial gene construct comprises genomic DNA or DNA encoding exons and one, two or more introns, wherein a nucleotide sequence encoding an intronic REMS, which may be upstream or downstream of a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site, is introduced into the nucleotide sequence encoding an intron by genetic engineering. In another aspect, an artificial gene construct comprises DNA encoding exons and one, two or more introns, wherein the nucleotide sequence encoding an intron comprises a nucleotide sequence encoding an intronic REMS, a nucleotide sequence encoding a 3′ splice site(s) and a nucleotide sequence encoding a branch point(s) sequence, wherein the nucleotide sequence encoding an intronic REMS, which may be upstream or downstream of at least one nucleotide sequence encoding a branch point and at least one nucleotide sequence encoding a 3′ splice site, is introduced into the nucleotide sequence encoding the intron by genetic engineering. In another aspect, an artificial gene construct comprises DNA encoding exons and one, two or more introns, wherein the nucleotide sequence encoding an intron comprises a nucleotide sequence encoding a 3′ splice site(s) and a nucleotide sequence encoding a branch point(s), wherein a nucleotide sequence encoding an intron is modified to introduce a nucleotide sequence encoding an intronic REMS. In some aspects, an artificial gene construct comprises a DNA sequence that is modified to introduce a nucleotide sequence encoding an intronic REMS, wherein the location of the intronic REMS is as illustrated in any of
(393) In certain aspects, an artificial gene construct is produced as follows: a nucleotide sequence encoding an intronic REMS is introduced into a nucleotide sequence encoding an existing intronic branch point and intronic 3′ splice site of genomic DNA or DNA, wherein the DNA encodes two or more exons and one or more introns, and wherein the nucleotide sequence encoding the intronic REMS is upstream of a nucleotide sequence encoding a branch point and a 3′ splice site. In some aspects, an artificial gene construct is produced as follows: a nucleotide sequence encoding an intronic REMS is introduced upstream of a nucleotide sequence encoding a branch point and a 3′ splice site of genomic DNA or DNA, wherein the DNA encodes two or more exons and an intron(s). In a specific aspect, the nucleotide sequence encoding the intronic REMS is introduced internally within a nucleotide sequence encoding an intron. In certain aspects, an artificial gene construct is produced as follows: a nucleotide sequence encoding an intronic REMS, a nucleotide sequence encoding a branch point, and a nucleotide sequence encoding a 3′ splice site are introduced into a cDNA, wherein the nucleotide sequence encoding the intronic REMS may be upstream of the branch point and 3′ splice site, respectively; or may be downstream of the 3′ splice site and branch point, respectively. The nucleotide sequence encoding the intronic REMS functions as a 5′ splice site. In certain aspects, the nucleotide sequence encoding the intronic REMS is internally within an intron. In a specific aspect, the genomic DNA or DNA chosen for use in the production of an artificial gene construct does not contain one or more of a nucleotide sequence encoding an intronic REMS or a nucleotide sequence encoding a branch point or a nucleotide sequence encoding a 3′ splice site. In certain aspects, the genomic DNA or DNA chosen for use in the production of an artificial gene construct contains an intronic REMS and an additional intronic REMS is introduced. In some aspects, care should be taken to introduce a nucleotide sequence encoding an intronic REMS into a DNA sequence so as not to disrupt an open reading frame or introduce a stop codon. The introduction of a nucleotide sequence encoding an intronic REMS into a DNA sequence may or may not result in an amino acid change at the protein level. In certain aspects, the introduction of a nucleotide sequence encoding an intronic REMS into a DNA sequence results in an amino acid change at the protein level. In some aspects, this amino acid change is a conservative amino acid substitution. In other aspects, the introduction of a nucleotide sequence encoding an intronic REMS into a DNA sequence does not result in an amino acid change at the protein level. Techniques known to one of skill in the art may be used to introduce an intronic REMS and other elements, such as a branch point sequence or 3′ splice site sequence into a DNA sequence, e.g., gene editing techniques such as the CRISPR-Cas approach, Transcription Activator-Like Effector Nucleases (TALENs), or Zinc finger nucleases (ZFNs) may be used.
(394) In certain aspects, an artificial gene construct comprises an RNA sequence comprising exons and one, two or more introns, wherein an intronic REMS 5′ splice site, which is downstream of a 3′ splice site, is introduced into an intron by genetic engineering. In another aspect, an artificial gene construct comprises an RNA sequence comprising exons and one, two, or more introns, wherein an intron comprises a 5′ splice site(s), a 3′ splice site(s) and a branch point(s), wherein an intronic REMS, which is upstream of a 3′ splice site, is introduced into an intron by genetic engineering. In another aspect, an artificial gene construct comprises an RNA sequence comprising exons and one, two, or more introns, wherein an intron comprises a 3′ splice site(s) and a branch point(s), wherein an intron is modified to introduce an intronic REMS. In specific aspects, the intronic REMS is non-endogenous, i.e., not naturally found in the RNA sequence of the artificial gene construct. In certain aspects, the artificial gene construct comprises other elements, such as a promoter (e.g., a tissue-specific promoter or constitutively expressed promoter), 5′ untranslated region, 3′ untranslated region, a binding site(s) for RNA binding protein(s) that regulate splice site (5′ and 3′) recognition and catalysis, a small molecule RNA sensor(s), e.g., riboswitches, stem-loop structures, and/or internal ribosome entry sites (IRES) and the like. In certain aspects, the artificial gene construct comprises at least the introns of a gene encoding a therapeutic protein. In some aspects, the artificial gene construct comprises at least the introns of a gene described herein. In a specific aspect, the RNA transcript chosen to be used in the production of an artificial gene construct does not contain an intronic REMS. In certain aspects, the RNA transcript chosen to use in the production of an artificial gene construct contains an intronic REMS and an additional exonic or intronic REMS is introduced. In other aspects, the artificial gene construct comprises at least one intron and two exons of a detectable reporter gene, such as green fluorescent protein (GFP), yellow fluorescent protein (YFP), red fluorescent protein, beta galactosidase, renilla luciferase, firefly luciferase, etc.
(395) In certain aspects, an artificial gene construct is produced as follows: an intronic REMS is introduced into an existing 5′ splice site of precursor RNA, wherein the RNA comprises two or more exons and one or more introns, and wherein an intronic REMS is upstream of a branch point sequence and a 3′ splice site sequence. In some aspects, an artificial gene construct is produced as follows: an intronic REMS is introduced upstream of a 3′ splice site of a precursor RNA, wherein the RNA comprises two or more exons and an intron(s). In a specific aspect, the intronic REMS is introduced internally within an intron. In certain aspects, an artificial gene construct is produced as follows: a branch point, a 3′ splice site and an intronic REMS are introduced into an mRNA, wherein the REMS may be either downstream or upstream of the branch point and 3′ splice site. The intronic REMS functions as a 5′ splice site. In certain aspects, the intronic REMS is located in an intron. In some aspects, care should be taken to introduce an intronic REMS into an RNA sequence so as not to disrupt an open reading frame or introduce a stop codon. The introduction of an intronic REMS into an RNA transcript may or may not result in an amino acid change at the protein level. In certain aspects, the introduction of an intronic REMS into an RNA transcript results in an amino acid change at the protein level. In some aspects, this amino acid change is a conservative amino acid substitution. In other aspects, the introduction of an intronic REMS into an RNA transcript does not result in an amino acid change at the protein level. Techniques known to one of skill in the art may be used to introduce an intronic REMS and other elements, such as a branch point or 3′ splice site into an RNA transcript.
(396) In some aspects, an artificial gene construct is present in a viral vector (e.g., an adeno-associated virus (AAV), self-complimentary adeno-associated virus (scAAV), adenovirus, retrovirus, lentivirus (e.g., Simian immunodeficiency virus, human immunodeficiency virus, or modified human immunodeficiency virus), Newcastle disease virus (NDV), herpes virus (e.g., herpes simplex virus), alphavirus, vaccina virus, etc.), a plasmid, or other vector (e.g., non-viral vectors, such as lipoplexes, liposomes, polymerosomes, or nanoparticles).
(397) In some aspects, the artificial gene construct is an RNA molecule modified to enable cellular uptake. In certain aspects, the artificial gene construct is an RNA molecule containing pseudouridine or other modified/artificial nucleotides for enhanced cellular uptake and gene expression.
(398) The use of an artificial gene construct described herein in gene therapy allows one to regulate the amount and type of a protein produced from the construct depending on the presence of a compound described herein. The compound is essentially a tunable switch that, depending on the amount and duration of the dose of the compound, regulates the amount and type of protein produced.
(399) In certain aspects, an RNA transcript transcribed from an artificial gene construct that is DNA would not produce or produce substantially less functional protein in the presence of a compound described herein than the amount of functional protein produced in the absence of a compound described herein. For example, if the artificial gene construct comprises a nucleotide sequence encoding an intronic REMS, which is downstream of an intronic nucleotide sequence encoding a 3′ splice site, then the creation of an intronic exon would ultimately result in less amount of the original protein (i.e., protein produced when RNA splicing is not modified) being produced in the presence of a compound described herein. Alternatively, in certain aspects, an RNA transcript transcribed from an artificial gene construct that is DNA would produce or would produce substantially less functional protein in the presence of a compound described herein than the amount of functional protein produced in the absence of a compound described herein.
(400) In certain aspects, an artificial gene construct or vector comprising an artificial gene construct is used in cell culture. For example, in a cell(s) transfected with an artificial gene construct or transduced with a vector comprising an artificial gene construct, the amount and type of a protein produced from the artificial gene construct can be modulated or modified depending upon whether or not a compound described herein is contacted with the transfected cell(s). For example, if the artificial gene construct comprises a nucleotide sequence encoding an intronic REMS, which is downstream of a nucleotide sequence encoding a 3′ splice site, then the likelihood of producing an intronic exon would be less in the absence of the compound relative to in the presence of the compound. Thus, the use of an artificial gene construct described herein allows one to regulate the amount and type of a protein produced from the construct depending on whether or not a compound described herein is present. In other words, a compound described herein is essentially a switch that regulates the amount and type of protein produced. This regulation of the production of protein could be useful, e.g., when trying to assess the role of certain genes or the effects of certain agents on pathways. The amount of the protein produced can be modified based on the amount of a compound described herein that is contacted with the transfected cell and/or how long the compound is contacted with the transfected cell.
(401) In certain aspects, an animal (e.g., a non-human animal, such as a mouse, rat, fly, etc.) is engineered to contain an artificial gene construct or a vector comprising an artificial gene construct. Techniques known to one of skill in the art may be used to engineer such animals. The amount of protein produced by this engineered animal can be regulated by whether or not a compound described herein is administered to the animal. The amount of the protein produced can be titrated based on the dose and/or the duration of administration of a compound described herein to the engineered animal. In certain aspects, the artificial gene construct encodes a detectable reporter gene, such as green fluorescent protein (GFP), yellow fluorescent protein (YFP), red fluorescent protein, beta galactosidase, renilla luciferase, firefly luciferase, etc. In accordance with this aspect, the engineered animal may be used to monitor development at different stages, visualize tissue function, etc. In other aspects, the artificial gene construct encodes a therapeutic gene product, such as described herein. In accordance with this aspect, the engineered animal may be used to monitor development at different stages or in functional biological studies where a certain protein or protein isoform needs to be expressed only for a period of time and not constitutively, etc.
(402) In certain aspects, an artificial gene construct or a vector comprising an artificial gene construct are used in gene therapy. Non-limiting examples of vectors include, but are not limited to, plasmids and viral vectors, such as vectors derived from replication defective retroviruses, adenoviruses, adeno-associated viruses and baculoviruses. The vector can be an RNA vector or preferably a DNA vector.
(403) Gene Therapy
(404) In another aspect, artificial gene constructs or vectors comprising an artificial gene construct may be provided for use in gene therapy. The use of an artificial gene construct described herein in gene therapy allows one to regulate the amount and type of a protein produced from the construct depending on whether or not a compound described herein is present. The compound is essentially a switch that regulates the amount and type of protein produced.
(405) In certain aspects provided herein, an RNA transcript transcribed from an artificial gene construct that is DNA would produce substantially more functional protein in the presence of a compound described herein than the amount of functional protein produced in the absence of a compound described herein. For example, an artificial gene construct or vector that comprises a nucleotide sequence encoding an intronic REMS, which is downstream of a nucleotide sequence encoding a branch point and a 3′ splice site, has a lower likelihood of producing an intronic exon in the absence of a compound described herein. If the protein produced as a result of iExon inclusion is a functional protein, then the result of compound administration would ultimately result in more of the functional protein being produced from the artificial gene construct. Thus, an artificial gene construct or a vector comprising an artificial gene construct may be useful in treating and/or preventing certain conditions or diseases associated with genes when the construct or vector increases the likelihood of producing an intronic exon in the presence of a compound described herein. The conditions or diseases may include those described herein.
(406) Alternatively, in certain aspects, an RNA transcript transcribed from an artificial gene construct that is DNA would produce substantially less functional protein in the presence of a compound described herein than the amount of functional protein produced in the absence of a compound described herein. For example, an artificial gene construct or vector that comprises a nucleotide sequence encoding an intronic REMS, has a higher likelihood of producing an intronic exon in the presence of a compound described herein. If the protein produced as a result of iExon inclusion is not a functional protein, but the protein produced without iExon inclusion is a functional protein, then the result of compound administration would result in reduction in the production of a functional protein. However, in the absence of a compound described herein, normal splicing would occur, and the production of the functional protein would not be reduced. The amount and type of the protein produced can be titrated based on dose and duration of dosing of the compound. In a specific aspect, the artificial gene construct used in gene therapy comprises an RNA sequence comprising two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the RNA nucleotide sequence of the intron comprises in 5′ to 3′ order: a first 5′ splice site, a first branch point, a first 3′ splice site, an iREMS, a second branch point and a second 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, and wherein r is adenine or guanine and n is any nucleotide.
(407) In another specific aspect, the artificial gene construct used in gene therapy comprises an RNA sequence comprising two exons and an intron, wherein a first exon is upstream of the intron and a second exon is downstream of the intron, wherein the RNA nucleotide sequence of the intron comprises in 5′ to 3′ order: an iREMS, a branch point and a 3′ splice site, wherein the iREMS comprises an RNA sequence GAgurngn, and wherein r is adenine or guanine and n is any nucleotide.
(408) In another specific aspect, the artificial gene construct used in gene therapy comprises an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in
(409) In another specific aspect, the artificial gene construct used in gene therapy comprises an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in
(410) In another specific aspect, the artificial gene construct used in gene therapy comprises an RNA sequence comprising two exons and an intron, wherein the RNA sequence comprises exonic and intronic elements illustrated in
(411) In another specific aspect, the artificial gene construct used in gene therapy comprises a DNA sequence encoding two exons and an intron, wherein the nucleotide sequence encoding a first exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding a second exon is downstream of the nucleotide sequence encoding the intron, wherein the nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding a first 5′ splice site, a nucleotide sequence encoding a first branch point, a nucleotide sequence encoding a first 3′ splice site, a nucleotide sequence encoding an iREMS, a nucleotide sequence encoding a second branch point and a nucleotide sequence encoding a second 3′ splice site, wherein the nucleotide sequence encoding the iREMS comprises a DNA sequence GAgtrngn, wherein r is adenine or guanine and n is any nucleotide.
(412) In another specific aspect, the artificial gene construct used in gene therapy comprises a DNA sequence encoding two exons and an intron, wherein the nucleotide sequence encoding a first exon is upstream of the nucleotide sequence encoding the intron and the nucleotide sequence encoding a second exon is downstream of the nucleotide sequence encoding the intron, wherein the nucleotide sequence encoding the intron comprises in 5′ to 3′ order: a nucleotide sequence encoding an iREMS, a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site, wherein the nucleotide sequence encoding the iREMS comprises an DNA sequence GAgtrngn, wherein r is adenine or guanine and n is any nucleotide.
(413) In another specific aspect, the artificial gene construct used in gene therapy comprises a DNA sequence encoding two exons and an intron, wherein the DNA sequence encodes exonic and intronic elements illustrated in
(414) In another specific aspect, the artificial gene construct used in gene therapy comprises a DNA sequence encoding two exons and an intron, wherein the DNA sequence encodes exonic and intronic elements illustrated in
(415) In another specific aspect, the artificial gene construct used in gene therapy comprises a DNA sequence encoding two exons and an intron, wherein the DNA sequence encodes exonic and intronic elements illustrated in
(416) An artificial gene construct, a vector comprising the artificial gene construct, or an RNA molecule comprising an artificial gene construct modified to enable cellular uptake may be introduced into cells or administered directly to patients. In one aspect, an artificial gene construct or a vector comprising the artificial gene construct is introduced into cells ex vivo or in vivo. In a specific aspect, an artificial gene construct or vector is introduced into a cell(s) ex vivo and the cell(s) may be administered to a subject. Various techniques known to one of skill in the art may be used to introduce an artificial gene construct or vector comprising the artificial gene construct into a cell(s), such as electroporation, transfection, transformation, etc. In another aspect, an artificial gene construct or vector comprising the artificial gene construct is administered to a subject. The artificial gene construct or vector comprising the artificial gene construct may be administered to a subject by any technique known to one skilled in the art, e.g., intramuscularly, intravenously, subcutaneously, intradermally, topically, intrathecally, intraperitoneally, intratumorally, etc. In some aspects, the artificial gene construct or vector comprising the artificial gene construct is administered to a subject systemically. In other aspects, the artificial gene construct or vector comprising the artificial gene construct is administered to a subject locally.
(417) Modifying Endogenous Genes
(418) In another aspect, provided herein are method for modifying an endogenous gene such that the resulting gene contains a nucleotide sequence encoding an intronic REMS, or contains an additional nucleotide sequence encoding an intronic REMS (in other words, an intronic REMS not naturally found in the endogenous gene, i.e., a non-endogenous intronic REMS). In a specific aspect, provided herein are methods for modifying an endogenous gene such that the resulting gene contains a nucleotide sequence encoding an intronic REMS and contains a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site upstream of the nucleotide sequence encoding the intronic REMS.
(419) As used herein, the term “endogenous gene” refers to a gene naturally found in a cell or living subject. Techniques known to one of skill in the art can be used to introduce any one, two, or all of the following: a branch point, a 3′ splice site, and an intronic REMS into an endogenous gene, e.g., the CRISPR-Cas approach, TALEN, or ZFN may be used. In certain aspects, a nucleotide sequence encoding an existing 5′ splice site can be replaced with an intronic REMS or an intronic REMS may be inserted internally within an intron. In some aspects, care should be taken to introduce a nucleotide sequence encoding an intronic REMS into an endogenous gene so as not to disrupt an open reading frame or introduce a stop codon. The introduction of a nucleotide sequence encoding an intronic REMS into an endogenous gene may or may not result in an amino acid change at the protein level. In certain aspects, the introduction of a nucleotide sequence encoding an intronic REMS into an endogenous gene results in an amino acid change at the protein level. In some aspects, this amino acid change is a conservative amino acid substitution. In other aspects, the introduction of a nucleotide sequence encoding an intronic REMS into an endogenous gene does not result in an amino acid change at the protein level.
(420) Kits
(421) In one aspect, provided herein are kits comprising, in a container, an artificial gene construct or a vector comprising an artificial construct. In certain aspects, the kits further comprise a compound described herein, in a separate container, and/or a negative control, such as phosphate buffered saline or a compound that does not recognize an intronic REMS, in a separate container. In a specific aspect, the kits further comprise a positive control, such as a compound described herein as a positive control. In some aspects, the kits further comprise primers and/or antibodies, in one or more separate containers, for assessing the production of an mRNA transcript from an artificial gene construct and/or protein production therefrom.
(422) In another aspect, provided herein are kits comprising, in one or more containers, the components and/or reagents necessary to produce an artificial gene construct and/or a vector comprising an artificial gene construct. In another aspect, provided herein are kits comprising, in one or more containers, the components and/or reagents necessary to modify an endogenous gene so that it contains a nucleotide sequence encoding an intronic REMS or an additional nucleotide sequence encoding an intronic REMS (in other words, a REMS not naturally found in the endogenous gene, i.e., a non-endogenous REMS). In another aspect, provided herein are kits comprising, in one or more containers, the components and/or reagents necessary to modify an endogenous gene so that the resulting gene contains a nucleotide sequence encoding an intronic REMS and contains a nucleotide sequence encoding a branch point and a nucleotide sequence encoding a 3′ splice site upstream of the nucleotide sequence encoding the intronic REMS. In some aspects, the kits further comprise primers and/or antibodies, in one or more separate containers, for assessing the production of an mRNA transcript from a modified endogenous gene and/or protein production therefrom.
(423) In another aspect, provided herein are kits comprising, in a container, a compound described herein, and instructions for use. In some aspects, the kits further comprise a negative control, such as phosphate buffered saline or a compound that does not recognize an intronic REMS, in a separate container.
EXAMPLES
(424) To describe in more detail and assist in understanding the present description, the following non-limiting biological examples are offered to more fully illustrate the scope of the description and are not to be construed as specifically limiting the scope thereof. Such variations of the present description that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are considered to fall within the scope of the present description and as hereinafter claimed. The example below illustrates the existence of an intronic recognition element for splicing modifier (REMS) that is important for the recognition of a compound described herein, and the binding of such a compound to the intronic REMS on a precursor RNA permits or enhances the splicing of the precursor RNA, and suggests the usefulness of the intronic REMS in combination with a compound described herein for modifying RNA splicing, and for modulating the amount of a gene product.
(425) Materials and Methods
(426) Cell Treatment:
(427) GM04856 lymphocyte cells were diluted in a medium composed of DMEM, 10% FBS and 1× Pen/Strep to a concentration of 2.5e5 cells/mL. 2 mL (500K cells) were seeded in 6-well plates and recovered for 4h at 37° C., 5% CO.sub.2. Compound dilutions were prepared as 2× compound stock in medium (e.g. for final 100 nM, make a 200 nM stock). After 4 h recovery, 2 mL of the 2× compound stock were added to each well, resulting in 4 mL/well with 1× final compound concentration. The cells were incubated for ˜20 h at 37° C., 5% CO.sub.2. After incubation, the cells were pelleted for 5 min at 1000 rpm. The supernatant was vacuum-removed and the cells were resuspended in 350 μL of RLT buffer (w/10 μL/mL beta-mercapto-ethanol, RNeasy kit). Total RNA was isolated using the RNeasy Mini Kit from Qiagen according to the manufacturer's instructions. The concentration of the resulting total RNA was determined using Nanodrop and diluted with water to a final concentration of 25 ng/μL.
(428) Endpoint RT-PCR and RNAseq:
(429) Analysis of alternatively spliced mRNAs in cultured cells
(430) SH-SY5Y cells derived from a bone marrow biopsy of a female patient with neuroblastoma were plated at 600,000 cells/well in 2 mL DMEM with 10% FBS in 6-well plates, and incubated for 4 hours in a cell culture incubator (37° C., 5% CO.sub.2, 100% relative humidity). Cells were then treated with Compound 64 at different concentrations (in 0.1% DMSO) for 24 hours. After removal of the supernatant, cells were lysed in RLT buffer with ß-mercaptoethanol and total RNA was extracted according to the manufacturer's protocol (RNeasy Mini Kit, Qiagen, Inc.).
(431) One-step RT-PCR was performed using AgPath-ID™ One-Step RT-PCR Reagents (Life Technologies, Inc.) using 50 ng total RNA as input. The following PCR conditions were used: Step 1: 48° C. (15 min), Step 2: 95° C. (10 min), Step 3: 95° C. (30 sec), Step 4: 55° C. (30 sec), Step 5: 68° C. (1 min), repeat Steps 3 to 5 for 34 cycles, then hold at 4° C. The presence of iExons within alternatively spliced mRNAs was identified using primers listed in Tables 13 through 19, which correspond to
(432) For RNAseq, SH-SY5Y cells were treated as described above. Total RNA (3 μg) was used for stranded RNA library preparation and sequencing. The mRNA was enriched using oligo(dT) beads and then fragmented randomly by adding fragmentation buffer, then the cDNA was synthesized by using mRNA template and random hexamers primer, after which a custom second-strand synthesis buffer (Illumina), dNTPs, RNase H and DNA polymerase I were added to initiate the second-strand synthesis. After a series of terminal repair, ligation and sequencing adaptor ligation, the double-stranded cDNA library was completed through size selection and PCR enrichment. RNA libraries were sequenced in a HiSeq sequencer at >30M per sample, then 150 nt pair end reads were generated. The adapter-sequence containing reads were removed and the remaining reads were mapped to human genome (hg19) using STAR (version 2.5.1). Only uniquely mapped reads (with MAPQ>10) with <5 nt/100 nt mismatches and properly paired reads were used. The number of reads in the coding sequence (CDS) region of protein-coding genes and exonic region of non-coding genes were counted and analyzed using DESeq2 (Love et al., 2014). For splicing analysis, reads were counted for different exons annotated or not annotated but identified from RNA-seq. for each exon, a Percent-Spliced-In (PSI) value was calculated using the percent of average read number supporting the inclusion of the exon among all reads supporting either the inclusion or the exclusion of an exon. PSI differences between two samples were compared and Fisher's Exact Test was used to determine statistical significance. A PSI increase of >5% and P-value <0.01 was used to select statistically significant intronic exons being included by the compound.
(433) Results:
(434) Oligonucleotides corresponding to exons that flank the intron where an iExon is located were used to amplify total RNA purified from untreated (DMSO) or cells treated with Compound 64 (at dose levels 10 nM, 1 μM or 10 μM).
(435) The resulting products were run on an agarose gel where the resulting bands of interest for each gene are shown by open and closed arrowheads, where an open arrowhead represents an exon isoform where endogenous wild-type splicing occurred; and, where a closed arrowhead represents an exon isoform where an iExon is included in the mRNA as shown in
(436) TABLE-US-00049 TABLE 13 Forward Primers for FIG. 2 Gene Forward Primer Sequence 5′-3′ SEQ ID NO: ABCB8 ABCB_54-73 GCCGGCGGCTCCTGTTTTAC 3635 ANXA11 ANXA_101-120 AGTCGCTGTACCACGACATC 3636 ARL15 ARL1_87-106-1a-KE GCTGCCGGATGTCTGATCTC 3637 ATG5 ATG5_100-122-KE ACGAATTCCAACTTGTTTCACGC 3638 BECN1 BECN_53-72 TTGACCATGCAATGGTGGCT 3639 C12orf4 c12o_40-58 GCCCAGGACTTCGGAACTA 3640 DENND4A DENN_79-98-KE GATCCGGGACAGCCCTTGTA 3641 DIAPH3 DIAP_6-25 CGGCAGAGTCTCAGTCCAAT 3642 EVC EVC_61-80-KE GGCACTGAGGCAGGAAAAGC 3643 FAM162A FAM1_54-72 GTCGGCGGAGTAGCAAGTG 3644 HTT HTT_E49_For TGCCCAGTCATTTGCACCTT 3645 MMS22L MMS22Le14F1 TGGTGTCTAAGAATGAGGAAATGGTA 3646 NIPA1 NIPA1e4R1 TTTGGGGAGTGGATAATCAGCA 3647 PAPD4 PAPD_46-65-KE CCCGGAGCAGTGATGGTGAT 3648 PDXDC1 PDXD_23-42 TGTGCCGTGTACCCTGTAAC 3649 RAF1 RAF1_90-112-KE CGACATCCACACCTAATGTCCAC 3650 SENP6 SENP_12-36-KE TCAGAGTCTAAGAGAGATGGAGGTT 3651 SF3B3 SF3B-9a_122-143-KE CTGGTTGATGAGTTGGACAGCC 3652 SF3B3 SF3B-2a_84-105-KE ACTTAACCTTGCAGAGAGCCAC 3653 TBCA TBCA_21-39-KE GCCTAAATAGCCGCAGCCT 3654 UBE2L3 UBE2_18-36 GCCAGCAGGAGGCTGATGA 3655 XRN2 XRN2_28-47 TTCACATCTGATGGCTCCCC 3656 ZFAND1 ZFAN_9-32-KE CCATTTGTGTGTGATGATTGTTCA 3657
(437) TABLE-US-00050 TABLE 14 Reverse Primers for FIG. 2 Gene Reverse Primer Sequence 5′-3′ SEQ ID NO: ABCB8 ABCB_235-254 AGGAGCTGCGGTAGCCATCA 3658 ANXA11 ANXA_302-321 GAGCCACCAGTCACTGTTCA 3659 ARL15 ARL1_392-411-1a-KE TGAGGCCTATGCAAACCAGG 3660 ATG5 ATG5_329-351-KE CAAGGAAGAGCTGAACTTGATGC 3661 BECN1 BECN_205-225 ACTGCCTCCTGTGTCTTCAAT 3662 C12orf4 c12o_329-349 TGACTGGCATTCTCTTGAACA 3663 DENND4A DENN_197-220-KE CCATACTTTTCAACAGTTCCTGGT 3664 DIAPH3 DIAP_242-261 GCGACTGGAGTCCTTGTTGA 3665 EVC EVC_217-238-KE AGGAAGAAGGTCAAGGAGGCAC 3666 FAM162A FAM1_314-336 CAGAGCTTCTGGTAAGCCTTAGA 3667 HTT HTT_E51_Rev GGGTATTTGTCCTTCTTTCT 3668 MMS22L MMS22Le15F1 CGCAAGTTGTGAGAAAGGCACTA 3669 NIPA1 NIPA1e3F1 GATGGTGTTCTGGATAAAAAGCCT 3670 PAPD4 PAPD_183-205-KE AAGGTGAGTATATGCCGTGCTTC 3671 PDXDC1 PDXD_179-199 CAAGCAACAGGGGCAGTCTTC 3672 RAF1 RAF1_249-269-KE GGCTACTGGACAGGGCTGAAG 3673 SENP6 SENP_158-177-KE TGATGAACGGAGCTGTTGGC 3674 SF3B3 SF3B-9a_283-303-KE CCCCTACCACAGGCCACATAC 3675 SF3B3 SF3B-2a_256-277-KE ATGTACTTTGCCAGTGTTGGGG 3676 TBCA TBCA_261-284-KE GTCATAATTTTCACCGTCTTCAGC 3677 UBE2L3 UBE2_163-182 AGCCCTTGCCAAGTCAATAA 3678 XRN2 XRN2_189-209 TTGTAGTACCGCTGCTTCCAG 3679 ZFAND1 ZFAN_146-167-KE AAGTTCTCTCTCAGCACAGTCT 3680
(438) TABLE-US-00051 TABLE 15 Forward Primers for FIG. 3 Gene Forward Primer Sequence 5′-3′ SEQ ID NO: ACVR1B ACVR_171-190KE TACCAGACGGTCATGCTGCG 3681 AXIN1 AXIN_198-217-KE AAAAGAGAGCCAGCCGAGCA 3682 CENPI CENP_177-201-KE TCATCCTTCTTTCTTGAGTTACGCT 3683 DCAF17 DCAF_84-103-KE TTATCGGCGCTGTGTCAGCA 3684 FAM174A FAM1_85-109-KE GGATGATGAGGATGATGACAACACG 3685 FBL FBL_99-118 TGCTCGACACCCACACAAAT 3686 GNG12 GNG1_17-39-KE ACCTGAAAACATTGGACCACACA 3687 GXYLT1 GXYL_57-77 GGAAGCAATTGCCAAGAAGCA 3688 HMGXB4 HMGX_829-848-KE CTCCCAGCATCCCATACGCT 3689 IVD IVD_40-60-KE CTGGGGATGAGGGGCTCTAAC 3690 KDM6A KDM6_94-116-KE TGGCACGAAATATCAAGGTCTCA 3691 MADD MADD_137-156-KE TGCCACAGGAAAGGGTCCTA 3692 MRPL45 MRP4_42-65 AGGACTTCCCTGAAAAAGCTAAGG 3693 NSUN4 NSUN_142-160-KE AGGGGGACACCTATGACCG 3694 NUPL1 NUPL_144-163 GTCCACAGGGTTCTCCTTCG 3695 PPIP5K2 PPIP_34-57-KE TCAGTTGACCTATCTCCCTCATGG 3696 SOS2 SOS2_86-107-KE AACCTCGAAACTGCAAACAGCC 3697 STAT1 STAT_68-88-KE TTCCTGCTGCGGTTCAGTGAG 3698 STRN3 STRN_95-115-KE GTGAAGGAGCTGGAGAAGCAC 3699 TNS3 TNS3_6-29-KE CCAGGTGATAAACTTGTGATCGTG 3700 WNK1 WNK1_45-67 GCTGGTGTTTTTAAGATGGGACT 3701
(439) TABLE-US-00052 TABLE 16 Reverse Primers for FIG. 3 Gene Reverse Primer Sequence 5′-3 SEQ ID NO: ACVR1B ACVR_399-418-KE TCAAACAGGGACCCGTGCTC 3702 AXIN1 AXIN_398-417-KE CCGCAGAAGTAGTACGCCAC 3703 CENPI CENP_257-281-KE CATTTACTGTCCTTTCTTCTGGGCT 3704 DCAF17 DCAF_251-274-KE GGGCATTCCCATAATAAAGCATCC 3705 FAM174A FAM1_197-221-KE GTTCTTTCATCAAAAGGCACATTCT 3706 FBL FBL_285-304 CCTCCATTACGCAGGAAGGT 3707 GNG12 GNG1_199-218-KE GGTGCTTGCTGTTTTGCTGG 3708 GXYLT1 GXYL_246-268 AGGAACGGATGTTGTCATCTTCA 3709 HMGXB4 HMGX_1123-1144-KE TTACAGAACACCTGGTAGGCCG 3710 IVD IVD_290-311-KE AGGTCCAGCCCACTCATCAGCA 3711 KDM6A KDM6_265-287-KE TGTCTGACATTGCTTCAGAGTTC 3712 MADD MADD_288-309-KE TCTCCTCTGTCTCACCAAGGTC 3713 MRPL45 MRP4_198-222 GGAAAACAGTGTTCAGTTACCAAGG 3714 NSUN4 NSUN_317-338-KE CTGTCGCTCCTTCTTCCTTGAC 3715 NUPL1 NUPL_306-325 AATTGAGCCCCACAGAAGGG 3716 PPIP5K2 PPIP_149-172-KE TTCACCTCCCCATTTTAGAACCAA 3717 SOS2 SOS2_281_301-KE AATGGTGTTGGGTGACCTCGT 3718 STAT1 STAT_279-300-KE TGCGAATGATGTCAGGGAAAGT 3719 STRN3 STRN_304-323-KE GAAGGGATGTGGGGCAGCTC 3720 TNS3 TNS3_96-116-KE CGGCTCCTTGTCCTTCAACAT 3721 WNK1 WNK1_187-207 CTGAGGACTCTGAGGTGCTGG 3722
(440) TABLE-US-00053 TABLE 17 Forward Primers for FIG. 4 Gene Forward Primer Sequence 5′-3′ SEQ ID NO: DCAF17 DECA_23-43-KE TGCTGTACCTTGCAGTGTTCC 3723 DHFR DHFR_5-24 CCATGAATCACCCAGGCCAT 3724 DMXL1 DMXL_157-177-KE GATTCACCACCCCACCCTGAT 3725 FER FER_90-114-KE ATCAGGTGTAGTTCTGCTGAATCCT 3726 FNDC3A FNDC_27-48-KE CCAAATGGTTCTGTGCCTCCTA 3727 GALC GALC_106-130-KE AGCGTTACCATGATTTGGACATTGA 3728 GBP1 GBP1_155-175-KE AGAAGTGCTAGAAGCCAGTGC 3729 HSD17B12 HSD1_40-63-KE TTTTGGATGTTCCTGACTTGGACA 3730 KIDINS220 KIDI_82-106-KE GAAAACATTCCTGCTCTGAAAGCTC 3731 LARP7 LARP_211-231-KE AGGATCCGGAGACGGAAATGT 3732 OXCT1 OXCT_55-75-KE GGCCTGACAGTGGATGACGTA 3733 SREK1 SREK_85-106-KE GCGAGTACGAGAAGCTCAGTCA 3734 SSBP1 SSBP_27-51 AAAAGAAAATAGAAGCCATGTTTCG 3735 STRADB STRA_58-78 TGTTCCACCAACGTTTCTCACTGTTCCACCAACGTTTCTCAC 3736
(441) TABLE-US-00054 TABLE 18 Reverse Primers for FIG. 4 Gene Reverse Primer Sequence 5′-3′ SEQ ID NO: DCAF17 DECA_168-190-KE CCATGAGACAAGGTAGCATCTGT 3737 DHFR DHFR_209-228 TGCCTTTCTCCTCCTGGACA 3738 DMXL1 DMXL_342-366-KE ATGACTACCACAAAGGCACTGATAA 3739 FER FER_189-213-KE TTGCCCAGTAATTCTCCCAATATGA 3740 FNDC3A FNDC_178-198-KE ACTGTGTGACTACCAGGGTGA 3741 GALC GALC_238-258-KE TTTCACTCGCTGGAGACCTTG 3742 GBP1 GBP1_354-374-KE CATTGGGCCTGTCATGTGGAT 3743 HSD17B12 HSD1_164-184-KE TGGATCTTTCCACCATGCCAG 3744 KIDINS220 KIDI_303-322-KE ATTGCCTTGTTCGGCAGCTA 3745 LARP7 LARP_366-387-KE CTGCAAGCACCTGTTTAACTCG 3746 OXCT1 OXCT_236-256-KE AATGAAAAACACGCAGCCTGG 3747 SREK1 SREK_335-355-KE GTATGGGAACGAGATCGACCG 3748 SSBP1 SSBP_300-323 TCTTTCAAGAACCAAACTGGTAGT 3749 STRADB STRA_353-372 GTTACCAGTGTTCCTGTGGG 3750
(442) TABLE-US-00055 TABLE 19 Forward Primers for FIG. 5 Gene Forward Primer Sequence 5′-3′ SEQ ID NO: ASAP1 ASAP_64-38-19a-KE TCACCAAAACCCACCCCTTC 3751 ATF6 ATF6_65-85 GAAGCCATCCGCAGAAGGGGA 3752 CRYL1 CRYL_36-56-KE CATGTCAGAAGGGTTGGGCAT 3753 CTNS CTNS_14-33 CCTCACTGTTCCTCCTGTCG 3754 DENND5A DENN_178-199-8a-KE CGGACACCTACTCTCCGTACAT 3755 DGKI KGKI_81-101-KE CCATGTGGAAAGAAACCCCGA 3756 DLGAP4 DLGA_281-301-KE AAGTGAACAAGGGACGCTGAC 3757 ELMO2 ELMO_53-72-KE TGCCACCACCGTCAGACATT 3758 ENTPD1 ENTP_79-97-KE TTGCTTGCTGTGGGGTTGAC 3759 ERGIC3 ERGI_128-147-KE GAAGGCTGCCAGGTGTATGG 3760 GNAQ GNAQ_143-164-KE CATGGACACACTCAAGATCCCA 3761 KIAA1524 KIAA_107-129-KE GGGATTTGGAACAAAGGTTGCAG 3762 KIAA1715 KIAA_2-26 TGAAGCATTGGATGATTTAAAATCC 3763 L3MBTL2 L3MB_47-67-KE TTACAAGGCTGCTCCCGTCAG 3764 LRRC42 LRCC_190-211 CCAGTGAATACTAGAGGGATCG 3765 MAN1A2 MAN1_24-46-KE ATTGGCTGAGAAACTCCTTCCTG 3766 MMS19 MMS1_22-45-KE CAGTGTTACAAGTTGTGGAAGCCC 3767 PMS1 PMS1_104-127-KE TCTCCTCATGAGCTTTGGTATCCT 3768 POMT2 POMT_10-29 ACCCTTCCTTCCCAGTGGAG 3769 PRPF31 RPRF_50-69-KE GCCAACCGTATGAGCTTCGG 3770 SKP1 SKP1_56-75 TCTTCCTTCGCTAACGCCTC 3771 STRN STRN_84-105-KE GAGAGAAAGGGAAAAAGGGGG 3772 STRN4 STRN_33-52-4a-KE GAGAACAGCCCGTTGGTGTG 3773 SUPT20H SUPT_8-30-KE AGCAAGGTTCAACCAGTCAAGAA 3774 TMEM214 TMEM_55-75 CCCACTTCTGGACTTTGCCTA 3775 UBAP2L UBAP_60-79-KE CCCTTTCCAACAGCCGAGTG 3776 VDAC2 VDAC_25-48 ATTGGAGTAGGCTATACTCAGACT 3777 VPS29 VPS2_12-31-K3 CGACGGTGGTGGTGACTGAG 3778
(443) TABLE-US-00056 TABLE 20 primers for FIG. 5 Gene Reverse Primer Sequence 5′-3′ SEQ ID NO: ASAP1 ASAP_323-347-19a-KE TGATGAAGTTGAACAGGTCTTCCTT 3779 ATF6 ATF6_230-254 TTGGTCTTGTGGTCTTGTTATGGGT 3780 CRYL1 CRYL_215-235-KE CTTCGCTGTATCTGTCGCAGT 3781 CTNS CTNS_251-271 TCGGGGAGCTCAAGGATAGTA 3782 DENND5A DENN_380-400-8a-KE TCAATTTTTGCCAGACGCAGC 3783 DGKI DGKI_257-278-KE ATGGGCATCAAATCCAAGGCTG 3784 DLGAP4 DLGA_466-485-KE CGGGACTGGGCTCCTCTTTT 3785 ELMO2 ELMO_229-248-KE TAATGGATGCCAGGGGCCGT 3786 ENTPD1 ENTP_198-219-KE AACTTGTGTGAGAAGAACCCGC 3787 ERGIC3 ERGI_321-340-KE CAGGGGGTTCACAATGCCTG 3788 GNAQ GNAQ_273-296-KE TTCTCAAAAGCAGACACCTTCTCC 3789 KIAA1524 KIAA_383-405-KE GCTTACTTCCATACCAGGAACCA 3790 KIAA1715 KIAA_2889-2909 TGAGTCCGGATCAAACCTTTC 3791 L3MBTL2 L3MB_447-467-KE TGAGCACCTCCACCTTCATCC 3792 LRRC42 LRCC_339-359 GTAAGACATTGCCTTGGTTGC 3793 MAN1A2 MAN1-4503-4522-KE AGCCCCAGTTTCGCCCTACT 3794 MMS19 MMS1_260-280-KE TTCTCCAGGAGCAAGGTGTGA 3795 PMS1 PMS1_285-308-KE ACATGAGAGCCATCTTGTGATCTG 3796 POMT2 POMT_151-170 CTGATAGTGCTTCCGGGTCA 3797 PRPF31 RPRF_218-237-KE TCGTTTACCTGTGTCTGCCG 3798 SKP1 SKP1_290-314 TGTGAAGATGAGTTCAGATCCAAAG 3799 STRN STRN_277-296-KE GGGTCTGGAAGGTGAACCCA 3800 STRN4 STRN_171-190-4a-KE TTGGACCGCATGTCGAGGAT 3801 SUPT20H SUPT_216-235-KE TGTTCTCGGCAGAGCCAAGC 3802 TMEM214 TMEM_173-193 AAATGCCAGCACTTTCAGTCG 3803 UBAP2L UBAP_218-237-KE CTCAGCCGTCCAGAAATGCT 3804 VDAC2 VDAC_147-168 AGCCCAACCTTGTGGCCTCCAG 3805 VPS29 VPS2_203-220-KE CCGGTGTGGGATGTGCAG 3806
(444) Results:
(445) The RNA-seq data iExon production (ΔPSI) according to the Fisher's Exact Test (FET) in SH-SY5Y cells treated with Compound 64 at 24 nM (Table 21) and 100 nM (Table 22) and in HD-1994 human normal fibroblast line cells treated with Compound 64 at 100 nM (Table 23) providing the Log 2 based fold change of gene expression (Log 2FC) for each, where NA represents “Not Available.” Analysis of RNA-seq data in HD1994 cells obtained from Palacino, et al., (Nat. Chem. Bio., 2015, (11) 511-517; NCBI-SRA Accession Number SRP055454).
(446) The ΔPSI for modulated expression of RNA transcripts identified is represented by stars in Table 21, Table 22 and Table 23, where one star (*) represents ≤25% change in expression, where two stars (**) represent change in expression in a range from >25% to ≤50% change, where three stars (***) represent change in expression in a range from >50% to ≤75% change, and, where four stars (****) represent change in expression in a range from >75% to ≤100% change.
(447) TABLE-US-00057 TABLE 21 Compound Effect in SHSY5Y Cells at 24 nm Inclusion Gene Position ΔPSI FET ΔPSI Log2FC ADAL i6 * 0.1 −0.1 ADAM23 i24 0.9 0.0 ADAM23 i24 * 0.03 0.0 ADAMTS19 i18 * 4.00E−10 −0.7 ADAMTS19 i10 * 1.00E−06 −0.7 AGPS 12 * 0.001 0.0 AKAP8L i1 * 0.03 0.0 ANKRD13C i6 * 1 0.0 ANXA11 i16 * 2.00E−14 −0.1 ARL15 i *** 2.00E−47 0.1 ARL15 i4 * 0.003 0.1 ARSJ i1 * 0.4 0.0 BECN1 i11 * 3.00E−76 0.0 BIN3 i2 * 5.00E−08 0.0 BTBD10 i4 * 0.03 −0.1 C11orf30 i20 * 3.00E−07 0.0 C12orf4 i1 ** 8.00E−40 0.1 C1orf27 i1 * 9.00E−05 0.1 C2orf47 i5 * 0.5 0.2 CACNB1 i6 * 0.02 0.0 CACNB4 i6 * 0.003 −0.1 CADM2 i4 * 1 0.1 CDH18 i4 ** 2.00E−04 0.0 CENPI i19 0.6 −0.1 CEP162 i2 * 3.00E−04 0.1 CEP170 i10 * 5.00E−15 −0.2 CEP192 i13 * 7.00E−04 0.1 CHEK1 i13 ** 2.00E−26 −0.3 CHRM2 i4 * 2.00E−05 −0.2 CMAHP i6 * 3.00E−04 −0.3 CNRIP1 i2 * 5.00E−44 0.1 CNTN1 i1 * 7.00E−15 −0.6 CRYBG3 i17 1 −0.1 CUX1 i2 * 8.00E−07 −0.1 DAAM1 i15 * 0.1 −0.1 DCAF17 12 * 7.00E−04 0.1 DCAF17 i6 * 0.4 0.1 DCUN1D4 i9 * 0.5 0.1 DDX42 i8 * 2.00E−14 0.0 DENND1A i10 * 0.2 −0.1 DENND4A i30 * 4.00E−05 −0.1 DENND5A i8 * 8.00E−04 −0.1 DET1 i1 * 0.08 0.0 DET1 i1 1 0.0 DGKI i19 * 0.4 −0.2 DHFR i5 ** 3.00E−07 −0.3 DHFR i5 ** 3.00E−11 −0.3 DIAPH3 i15 * 9.00E−11 −0.4 DIAPH3 i27 * 5.00E−05 −0.4 DLG5 i20 * 6.00E−08 −0.1 DYRK1A i3 * 6.00E−05 0.1 DZIP1L i15 * 0.02 −0.2 ELMO2 i3 **** 0.004 0.0 ENAH i1 * 1.00E−17 0.3 ENOX1 i5 * 0.3 0.0 ERC2 i6 1 −0.1 EVC i5 * 2.00E−11 −0.1 FAM162A i1 * 4.00E−26 0.1 FAM174A i2 * 2.00E−04 0.0 FAM195B i5 0.8 0.0 FAM208B i1 * 0.006 0.1 FAM69B i1 * 9.00E−05 0.1 FBXL16 i2 * 5.00E−09 −0.4 FGD4 i1 * 0.1 −0.1 FHOD3 i21 * 2.00E−07 −0.9 GALC i6 * 0.09 −0.2 GLCE i2 1 0.0 GOLGB1 i14 * 0.1 −0.2 GTSF1 i2 * 0.003 0.0 GXYLT1 i7 * 7.00E−43 0.1 HDAC5 i14 * 0.09 −0.3 HDX i1 ** 1.00E−11 0.2 HTT i49 * 1.00E−21 −1.0 IFT57 i5 * 2.00E−15 0.2 INO80 i27 * 6.00E−05 0.0 INVS i3 * 3.00E−07 0.0 KDM6A i27 * 1.00E−16 0.2 KIDINS220 i2 * 0.008 0.0 KIF21A i1 * 1.00E−21 0.0 L3MBTL2 i5 * 0.09 −0.4 LINCR-0002 i1 * 1.00E−07 0.0 LINGO2 i6 * 3.00E−05 −0.2 LOC400927 i3 ** 0.02 0.0 LPHN1 i3 * 5.00E−11 0.0 LRRC1 i11 * 0.02 −0.1 LRRC42 i2 ** 3.00E−35 0.0 LYRM1 i2 * 2.00E−12 0.2 MACROD2 i1 * 0.01 −0.1 MAPK10 i2 * 0.1 0.0 MARCH8 i6 * 1.00E−04 0.0 MDN1 i91 * 0.1 0.0 MEAF6 i8 ** 1.00E−12 0.1 MEMO1 i6 * 1.00E−17 −0.1 MFN2 i1 * 2.00E−08 0.0 MLLT10 i17 * 4.00E−11 0.0 MRPL39 i10 * 3.00E−06 0.1 MRPL45 i4 * 1.00E−09 0.1 MRPS28 i2 * 6.00E−12 0.1 MTMR3 i6 * 0.05 0.0 MYB i11 * 0.03 0.1 MYCBP2 i55 ** 2.00E−08 0.0 MYCBP2 i80 * 0.01 0.0 MYLK i5 1 −0.1 NLGN1 i4 1 −0.1 NSUN4 i5 * 0.5 0.0 NUPL1 i1 * 5.00E−45 0.2 OSBPL3 i1 * 0.3 0.0 PAPD4 i7 ** 1.00E−24 −0.4 PCDH10 i1 * 0.002 −0.2 PDE3A i2 * 6.00E−12 −0.1 PDE7A i2 ** 4.00E−40 0.2 PDXDC1 i7 * 3.00E−21 −0.1 PDXDC2P i7 *** 0.01 0.0 PELI1 i1 * 3.00E−05 0.0 PITPNB i7 * 3.00E−10 −0.5 PMS1 i5 * 0.2 0.0 POMT2 i11 ** 5.00E−76 0.0 PSMA4 i4 * 3.00E−26 0.2 RAB23 i1 * 0.2 0.2 RAF1 i7 * 1.00E−28 0.0 RASIP1 i3 1 0.0 RCOR3 i10 * 3.00E−07 0.0 RERE i13 * 0.04 0.1 RNF130 i8 * 0.05 0.1 RNF144A i2 * 0.008 −0.1 RNF213 i26 * 0.3 −0.3 RPF2 i1 * 1.00E−10 0.3 RPS10 i5 * 0.02 0.0 SCO1 i4 * 6.00E−06 −0.1 SENP6 i2 * 2.00E−23 0.1 SF3B3 i2 * 5.00E−164 0.0 SGMS1 i2 * 0.5 0.1 SGPL1 i3 * 0.5 −0.1 SLC25A16 i6 * 0.04 0.0 SLC25A17 i3 * 7.00E−10 0.0 SNX24 i1 * 5.00E−08 −0.1 SNX7 i8 * 4.00E−12 0.1 SORCS1 i26 * 0.03 −0.2 SPIDR i1 * 3.00E−07 0.0 SPRYD7 i4 * 5.00E−06 −0.1 SREK1 i7 * 2.00E−08 −0.2 SSBP1 i2 * 3.00E−104 0.1 STRADB i4 * 6.00E−06 0.0 STXBP4 i16 1 0.0 SUPT20H i24 * 4.00E−08 0.0 TAF2 i23 ** 4.00E−42 0.1 TARBP1 i13 * 0.2 0.0 TASP1 i13 * 1.00E−04 −0.1 TBCA i1 * 6.00E−88 0.1 TCF4 i4 * 7.00E−50 −0.1 TEKT4P2 i2 0.9 0.0 TET1 i8 * 3.00E−09 −0.2 TIAM1 i4 * 1.00E−07 −0.1 TJP2 i1 * 8.00E−06 0.2 TMEM214 i8 * 6.00E−06 0.0 TNRC6A i4 * 1.00E−27 0.0 TRAF3 i8 * 0.1 0.0 TRIM65 i5 ** 1.00E−22 0.0 TSPAN7 i1 * 0.02 −0.3 UBN2 i6 * 0.6 −0.1 URGCP-MRPS24 i1 * 7.00E−06 0.0 UVRAG i5 * 0.006 −0.1 WDR27 i9 ** 1.00E−29 −0.1 WDR90 i9 * 6.00E−06 −0.2 WNK1 i23 * 4.00E−31 0.0 XRN2 i16 * 1.00E−24 −0.5 ZFP82 i4 * 5.00E−16 0.1 ZMIZ2 i1 * 0.001 0.0 ZNF138 i3 * 1.00E−05 0.1 ZNF208 i3 * 0.4 0.0 ZNF212 i1 * 0.01 0.1 ZNF280D i19 * 0.2 0.0 ZNF37BP i4 *** 1.00E−31 0.0 ZNF426 i4 * 0.01 0.2 ZNF618 i11 * 2.00E−09 −0.1 ZNF680 i3 * 2.00E−09 0.1 ZNF730 i3 * 0.04 0.1 ZNF836 i3 * 0.08 −0.1 ZSCAN25 i2 * 0.02 0.0
(448) TABLE-US-00058 TABLE 22 Compound Effect in SHSY5Y Cells at 100 nm Inclusion Gene Position ΔPSI FET ΔPSI Log2FC ADAL i6 * 7.00E−11 −0.4 ADAM23 i24 * 9.00E−13 0.0 ADAM23 i24 * 2.00E−12 0.0 ADAMTS19 i18 ** 2.00E−23 −1.3 ADAMTS19 i10 * 8.00E−23 −1.3 AGPS i2 * 4.00E−14 −0.3 AKAP8L i1 * 2.00E−19 −0.1 ANKRD13C i6 * 6.00E−05 −0.1 ANXA11 i16 * 1.00E−66 −0.6 ARL15 i1 **** 9.00E−90 0.1 ARL15 i4 * 6.00E−04 0.1 ARSJ i1 * 2.00E−04 0.0 BECN1 i11 ** 3.00E−249 0.2 BIN3 i2 * 1.00E−18 0.0 BTBD10 i4 * 1.00E−13 −0.3 C11orf30 i20 * 6.00E−20 −0.1 C12orf4 i1 **** 2.00E−93 0.2 C1orf27 i1 * 9.00E−32 0.2 C2orf47 i5 * 2.00E−05 0.1 CACNB1 i6 * 2.00E−05 0.1 CACNB4 i6 ** 5.00E−10 0.0 CADM2 i4 ** 0.006 0.0 CDH18 i4 **** 1 0.0 CENPI i19 * 1.00E−10 0.0 CEP162 i2 * 1.00E−10 0.2 CEP170 i10 * 5.00E−43 −0.6 CEP192 i13 * 0.002 0.1 CHEK1 i13 ** 9.00E−34 −0.6 CHRM2 i4 ** 9.00E−14 0.1 CMAHP i6 ** 2.00E−05 −0.3 CNRIP1 i2 * 7.00E−122 0.1 CNTN1 i1 * 3.00E−61 0.0 CRYBG3 i17 * 6.00E−08 −0.1 CUX1 i2 * 1.00E−33 −0.1 DAAM1 i15 * 6.00E−05 −0.1 DCAF17 i2 * 7.00E−14 0.1 DCAF17 i6 * 5.00E−08 0.1 DCUN1D4 i9 * 9.00E−06 0.0 DDX42 i8 * 1.00E−54 −0.2 DENND1A i10 * 5.00E−12 −0.3 DENND4A i30 ** 3.00E−19 0.0 DENND5A i8 * 7.00E−35 −0.6 DET1 i1 * 0.002 0.0 DET1 i1 * 6.00E−04 0.0 DGKI i19 * 2.00E−05 −0.3 DHFR i5 ** 2.00E−10 −0.8 DHFR i5 ** 4.00E−17 −0.8 DIAPH3 i15 * 5.00E−19 −1.1 DIAPH3 i27 * 1.00E−27 −1.1 DLG5 i20 * 2.00E−43 −0.4 DYRK1A i3 * 2.00E−10 0.1 DZIP1L i15 * 5.00E−05 −0.2 ELMO2 i3 **** 5.00E−04 0.0 ENAH i1 * 8.00E−71 0.2 ENOX1 i5 * 2.00E−07 0.0 ERC2 i6 *** 9.00E−05 −0.1 EVC i5 ** 5.00E−27 −0.2 FAM162A i1 * 9.00E−88 0.1 FAM174A i2 * 8.00E−10 0.0 FAM195B i5 * 5.00E−08 −0.2 FAM208B i1 * 7.00E−06 0.1 FAM69B i1 * 8.00E−06 −0.1 FBXL16 i2 * 5.00E−13 −0.5 FGD4 i1 * 4.00E−17 0.0 FHOD3 i21 *** 5.00E−37 −1.2 GALC i6 * 4.00E−05 −0.7 GLCE i2 * 0.001 0.1 GOLGB1 i14 * 2.00E−04 −0.1 GTSF1 i2 1 −0.1 GXYLT1 i7 ** 2.00E−103 0.1 HDAC5 i14 * 9.00E−07 −0.5 HDX i1 *** 1.00E−37 0.3 HTT i49 *** 9.00E−62 −1.4 IFT57 i5 * 3.00E−45 0.1 INO80 i27 * 6.00E−15 −0.1 INVS i3 * 2.00E−10 0.1 KDM6A i27 *** 3.00E−47 0.3 KIDINS220 i2 * 2.00E−12 0.1 KIF21A i1 * 3.00E−79 −0.1 L3MBTL2 i5 * 3.00E−11 −0.9 LINCR-0002 i1 * 7.00E−12 0.0 LINGO2 i6 * 1.00E−05 0.0 LOC400927 i3 *** 3.00E−06 0.0 LPHN1 i3 * 2.00E−20 −0.2 LRRC1 i11 * 3.00E−09 −0.3 LRRC42 i2 *** 1.00E−92 0.0 LYRM1 i2 * 1.00E−56 0.4 MACROD2 i1 *** 3.00E−06 0.1 MAPK10 i2 * 4.00E−07 −0.1 MARCH8 i6 * 5.00E−04 0.1 MDN1 i91 * 2.00E−10 −0.1 MEAF6 i8 *** 3.00E−23 0.0 MEMO1 i6 ** 1.00E−62 −0.5 MFN2 i1 * 1.00E−33 0.0 MLLT10 i17 * 3.00E−41 −0.2 MRPL39 i10 * 3.00E−32 0.2 MRPL45 i4 * 3.00E−26 0.1 MRPS28 i2 * 1.00E−29 0.0 MTMR3 i6 * 1.00E−05 0.0 MYB i11 * 8.00E−07 −0.1 MYCBP2 i55 ** 5.00E−13 0.1 MYCBP2 i80 * 3.00E−08 0.1 MYLK i5 * 9.00E−06 −0.1 NLGN1 i4 * 4.00E−04 −0.2 NSUN4 i5 * 2.00E−10 −0.3 NUPL1 i1 ** 2.00E−125 0.3 OSBPL3 i1 * 2.00E−05 0.1 PAPD4 i7 *** 3.00E−58 −0.7 PCDH10 i1 * 1.00E−10 −0.2 PDE3A i2 * 2.00E−39 0.0 PDE7A i2 *** 1.00E−122 0.3 PDXDC1 i7 ** 4.00E−67 −0.3 PDXDC2P i7 **** 1.00E−05 0.0 PELI1 i1 * 5.00E−11 0.0 PITPNB i7 * 2.00E−28 −1.5 PMS1 i5 * 8.00E−22 −0.4 POMT2 i11 **** 4.00E−165 −0.2 PSMA4 i4 * 5.00E−69 0.2 RAB23 i1 * 7.00E−07 0.1 RAF1 i7 * 1.00E−104 0.0 RASIP1 i3 **** 0.01 0.0 RCOR3 i10 * 5.00E−19 −0.2 RERE i13 * 3.00E−19 −0.1 RNF130 i8 * 2.00E−04 0.1 RNF144A i2 * 2.00E−17 0.1 RNF213 i26 * 0.002 −0.1 RPF2 i1 * 2.00E−41 0.2 RPS10 i5 * 0.005 0.0 SCO1 i4 * 3.00E−21 −0.4 SENP6 i2 ** 1.00E−103 0.0 SF3B3 i2 * 0 −0.1 SGMS1 i2 * 5.00E−05 0.1 SGPL1 i3 * 3.00E−04 0.1 SLC25A16 i6 * 7.00E−06 −0.1 SLC25A17 i3 * 2.00E−39 0.0 SNX24 i1 * 3.00E−16 0.1 SNX7 i8 * 1.00E−75 0.1 SORCS1 i26 * 5.00E−05 −0.3 SPIDR i1 ** 1.00E−29 0.0 SPRYD7 i4 * 2.00E−12 −0.2 SREK1 i7 * 6.00E−32 −0.6 SSBP1 i2 * 0 0.0 STRADB i4 * 8.00E−16 0.1 STXBP4 i16 * 1.00E−10 0.1 SUPT20H i24 * 9.00E−24 0.0 TAF2 i23 *** 3.00E−99 0.1 TARBP1 i13 * 0.005 −0.2 TASP1 i13 * 2.00E−07 0.0 TBCA i1 * 5.00E−244 0.1 TCF4 i4 * 8.00E−125 0.0 TEKT4P2 i2 * 0.007 0.0 TET1 i8 *** 3.00E−18 −0.4 TIAM1 i4 *** 4.00E−22 −0.1 TJP2 i1 * 2.00E−25 −0.1 TMEM214 i8 * 3.00E−50 −0.1 TNRC6A i4 ** 6.00E−90 0.0 TRAF3 i8 * 4.00E−10 −0.2 TRIM65 i5 ** 6.00E−28 −0.1 TSPAN7 i1 * 2.00E−06 −0.4 UBN2 i6 * 0.003 −0.2 URGCP-MRPS24 i1 ** 2.00E−19 0.0 UVRAG i5 * 9.00E−06 −0.2 WDR27 i9 *** 9.00E−64 −0.2 WDR90 i9 ** 2.00E−16 −0.2 WNK1 i23 * 3.00E−86 0.0 XRN2 i16 * 3.00E−78 −1.1 ZFP82 i4 ** 2.00E−38 0.4 ZMIZ2 i1 * 1.00E−20 0.1 ZNF138 i3 * 2.00E−20 0.1 ZNF208 i3 * 0.005 0.0 ZNF212 i1 * 2.00E−10 0.0 ZNF280D i19 * 0.007 0.0 ZNF37BP i4 **** 6.00E−49 0.1 ZNF426 i4 * 2.00E−18 0.3 ZNF618 i11 ** 3.00E−37 0.0 ZNF680 i3 ** 7.00E−35 0.2 ZNF730 i3 * 5.00E−08 0.1 ZNF836 i3 * 1.00E−04 0.1 ZSCAN25 i2 * 2.00E−10 0.0
(449) TABLE-US-00059 TABLE 23 Compound Effect in HD-1994 Cells at 100 nm Inclusion Gene Position ΔPSI FETΔPSI Log2FC ABHD10 i4 * 7.00E−22 0.2 ADAM17 i1 * 2.00E−11 −0.4 AGPAT4 i1 * 1.00E−06 −0.1 AGPS i2 ** 1.00E−51 −1.6 AKT1 i1 ** 7.00E−36 −0.1 ANKRD13C i6 * 4.00E−19 −0.6 ANXA11 i16 ** 1.00E−185 −1.4 APIP i1 * 2.00E−25 0.1 APPL2 i1 * 2.00E−28 −2.2 ARHGAP1 i1 * 8.00E−63 −0.7 ARHGAP5 i5 ** 5.00E−60 −0.1 ARL15 i1 **** 9.00E−28 −0.3 ARL15 i4 ** 3.00E−08 −0.3 ARL5B i5 * 1.00E−04 0.0 ASAP1 i12 **** 3.00E−110 −2.0 ASAP1 i19 * 5.00E−07 −2.0 ATF6 i14 ** 2.00E−71 0.0 BECN1 i11 *** 0 0.1 BHMT2 i2 *** 4.00E−19 −0.4 BIN3 i2 ** 3.00E−41 −0.1 BNC2 i3 * 5.00E−07 −0.2 BTBD10 i4 * 3.00E−16 −1.0 C10orf76 i25 * 4.00E−18 −0.2 C11orf30 i20 ** 7.00E−09 −0.6 C11orf73 i2 ** 2.00E−12 −0.9 C12orf4 i1 **** 9.00E−137 0.0 C1orf27 i1 *** 3.00E−52 0.1 C1QTNF9B-AS1 i1 * 0.002 0.1 CCNL2 i5 * 0.003 0.0 CDH18 i4 ** 1.00E−07 −0.7 CENPI i19 ** 7.00E−24 −0.1 CEP57 i1 * 6.00E−13 −0.2 CMSS1 i1 * 2.00E−27 −0.1 CNOT7 i2 * 1.00E−04 0.0 COPS7B i2 * 1.00E−16 −0.5 CRISPLD2 i1 * 3.00E−06 −0.6 CUX1 i2 * 6.00E−12 −0.3 DCAF17 i2 ** 3.00E−14 −0.9 DDX42 i8 * 1.00E−32 −1.7 DENND4A i30 ** 9.00E−16 0.2 DENND5A i8 * 1.00E−43 −1.9 DENND5A i3 * 4.00E−22 −1.9 DET1 i1 * 7.00E−04 0.0 DLG5 i20 * 2.00E−13 −1.5 DMXL1 i25 * 3.00E−06 0.0 DNAJA4 i2 * 0.001 −0.3 DNMBP i1 * 4.00E−05 −0.1 ENAH i1 *** 9.00E−267 0.2 EP300 i1 * 2.00E−16 0.2 ERC1 i18 * 9.00E−29 −0.4 EVC i5 **** 1 00E−54 0.2 EXOC3 i12 * 4.00E−14 −0.6 EXOC6B i21 ** 1.00E−20 0.0 FAM162A i1 ** 1.00E−50 −0.2 FAM174A i2 ** 3.00E−22 0.5 FAM208B i1 ** 2.00E−08 0.2 FAM49B i1 * 3.00E−10 −0.2 FBN2 i5 * 2.00E−78 −0.6 GBP1 i1 * 7.00E−14 −0.2 GNG12 i2 * 2.00E−152 −0.1 GXYLT1 i7 **** 5.00E−86 −1.0 HDX i1 **** 6.00E−10 0.5 HMGXB4 i6 * 3.00E−18 −0.2 HOXB3 i1 ** 1.00E−05 0.1 HSD17B4 i2 * 3.00E−57 0.0 IFT57 i5 ** 4.00E−97 0.0 IKBKAP i1 * 1.00E−05 0.0 INO80 i27 * 1.00E−07 −0.9 INPP4B i11 * 0.001 −0.2 ITCH i2 * 3.00E−05 −0.5 IVD i7 ** 7.00E−54 −0.4 KDM6A i27 **** 1.00E−43 −0.2 KDSR i9 * 2.00E−21 −1.6 KIAA1524 i11 *** 1.00E−17 −3.2 KIAA1715 i6 ** 2.00E−53 −1.7 KIDINS220 i2 ** 5.00E−33 0.2 L3MBTL2 i5 * 4.00E−04 −2.9 LGALS3 i1 * 2.00E−143 −0.7 LOC400927 i3 *** 0.002 −0.1 LRRC42 i2 *** 1.00E−103 −0.2 LYRM1 i2 *** 1.00E−56 0.3 MACROD2 i1 **** 4.00E−04 −0.2 MANEA i1 * 1.00E−21 −0.3 MARCH7 i8 * 6.00E−26 −0.3 MARCH8 i6 * 5.00E−08 0.0 MEAF6 i8 **** 3.00E−11 −0.2 MEMO1 i6 **** 2.00E−35 −1.2 MFN2 i1 *** 3.00E−127 0.1 MMS19 i2 * 5.00E−21 −1.8 MORF4L1 i9 *** 0.002 0.0 MRPL39 i10 * 2.00E−36 0.2 MRPL45 i4 * 5.00E−34 0.1 MRPS28 i2 * 6.00E−10 −0.1 MYCBP2 i55 ** 1.00E−08 −0.2 MYCBP2 i80 ** 1.00E−16 −0.2 MYLK i5 * 3.00E−45 −0.4 MZT1 i1 * 3.00E−67 −0.3 NEDD4 i21 * 2.00E−11 −0.2 NFASC i28 * 1.00E−12 0.0 NGF i1 *** 4.00E−150 0.4 NIPA1 i3 * 3.00E−04 0.0 NLN i12 * 5.00E−15 −1.4 NREP i3 * 1.00E−13 −0.3 NUPL1 i1 *** 4.00E−146 0.3 OSBPL3 i1 * 3.00E−11 −0.1 PAPD4 i7 *** 6.00E−61 −1.9 PBX3 i8 * 1.00E−09 −0.2 PDE7A i2 *** 9.00E−25 −0.5 PIGN i22 * 8.00E−24 0.1 PITPNB i7 * 2.00E−04 −4.0 PNISR i1 * 2.00E−17 −0.1 POMT2 i11 **** 1.00E−182 0.0 PPARG i4 * 5.00E−09 −0.5 PPFIBP1 i2 * 8.00E−13 0.0 PRPF31 i11 * 6.00E−27 0.1 PSMA4 i4 * 2.00E−14 0.1 PXK i1 * 2.00E−08 −0.2 RAB23 i1 * 1.00E−16 −0.7 RAFI i7 * 2.00E−102 −0.1 RAPGEF1 i11 * 2.00E−18 0.0 RBBP8 i6 * 5.00E−16 −1.4 RERE i13 *** 3.00E−48 −0.1 RGL1 i1 * 3.00E−05 −0.2 RPF2 i1 * 1.00E−51 0.1 SAMD4A i3 * 3.00E−18 −0.2 SCO1 i4 * 8.00E−26 −1.3 SENP6 i2 **** 3.00E−77 −0.5 SF3B3 i2 *** 0 −0.1 SGIP1 i1 * 7.00E−12 −0.1 SH2B3 i2 * 2.00E−07 0.1 SKP1 i1 * 2.00E−115 −0.7 SLC12A2 i10 * 1.00E−08 −0.1 SLC25A17 i3 ** 7.00E−66 −0.4 SMOX i1 * 9.00E−06 0.0 SNAP23 i3 * 2.00E−27 −0.7 SNX24 i1 ** 7.00E−27 0.1 SNX7 i8 ** 8.00E−203 −0.1 SOCS6 i1 * 0.001 −0.1 SOGA2 i15 * 2.00E−05 NA SPIDR i1 ** 7.00E−19 −0.3 SSBP1 i2 * 7.00E−75 −0.3 STRADB i4 ** 2.00E−27 0.2 STXBP6 i1 *** 1.00E−39 −0.5 STXBP6 i2 * 4.00E−21 −0.5 SUPT20H i24 * 2.00E−23 −0.5 TAF2 i23 *** 3.00E−58 −0.6 TAF2 i20 * 2.00E−07 −0.6 TASP1 i13 ** 5.00E−12 −0.3 TBCA i1 **** 6.00E−246 −0.3 TBL1XR1 i1 * 7.00E−09 −0.2 TCF4 i4 ** 3.00E−42 0.0 TJAP1 i3 * 0.003 0.1 TJP2 i1 * 1.00E−22 0.0 TMEM214 i8 ** 0 0.0 TMX3 i5 * 2.00E−39 −0.7 TNRC6A i4 **** 9.00E−54 0.0 TXNL4B i1 * 4.00E−06 −0.1 UBE2D3 i1 ** 9.00E−07 −0.1 UBE2L3 i1 **** 9.00E−54 0.2 UNC13B i7 * 4.00E−04 0.0 URGCP-MRPS24 i1 *** 7.00E−45 0.1 VDAC2 i10 **** 1.00E−08 0.1 WHSC2 i1 * 5.00E−14 NA WNK1 i23 *** 1.00E−152 0.0 XRN2 i16 ** 3.00E−26 −3.9 ZFP82 i4 **** 1.00E−26 0.8 ZNF138 i3 **** 8.00E−12 −0.2 ZNF350 i4 *** 5.00E−07 0.8 ZNF37BP i4 **** 1.00E−05 −0.2 ZNF618 i11 ** 9.00E−12 −0.2 ZNF680 i3 *** 2.00E−06 −0.4 ZNF777 i1 ** 0.001 −0.1 ZNF804A i1 * 3.00E−08 −0.1 ZSCAN25 i2 * 2.00E−04 −0.1
(450) Details on the location of the iExon produced in affected genes from Table 21, Table 22 and Table 23 are shown in Table 24.
(451) TABLE-US-00060 TABLE 24 Gene Coordinates Gene Coordinates (hg19) Refseqid Description ABHD10 chr3: +: 111709547: NM_018394 abhydrolase domain containing 10 111709598 ADAL chr15: +: 43629554: NM_001159280 adenosine deaminase-like 43629613 ADAM17 chr2: −: 9683889: NM_003183 ADAM metallopeptidase domain 17 9683825 ADAM23 chr2: +: 207470514: NM_003812 ADAM metallopeptidase domain 23 207470604 ADAM23 chr2: +: 207472682: NM_003812 ADAM metallopeptidase domain 23 207472728 ADAMTS19 chr5: +: 129023788: NM_133638 ADAM metallopeptidase with 129023907 thrombospondin type 1 motif, 19 ADAMTS19 chr5: +: 128959360: NM_133638 ADAM metallopeptidase with 128959434 thrombospondin type 1 motif, 19 AGPAT4 chr6: −: 161687802: NM_020133 1-acylglycerol-3-phosphate O- 161687740 acyltransferase 4 (lysophosphatidic acid acyltransferase, delta) AGPS chr2: +: 178297714: NM_003659 alkylglycerone phosphate synthase 178297852 AKAP8L chr19: −: 15524082: NR_111971 A kinase (PRKA) anchor protein 8- 15523995 like AKT1 chr14: −: 105261053: NM_001014432 v-akt murine thymoma viral 105260902 oncogene homolog 1 ANKRD13C chr1: −: 70767766: NM_030816 ankyrin repeat domain 13C 70767706 ANXA11 chr10: −: 81916254: NM_001278407 annexin A11 81916134 ANXA11 chr10: −: 81916235: NM_145869 annexin A11 81916134 APIP chr11: −: 34933660: NM_015957 APAF1 interacting protein 34933520 APPL2 chr12: −: 105625259: NM_018171 adaptor protein, phosphotyrosine 105625147 interaction, PH domain and leucine zipper containing 2 ARHGAP1 chr11: −: 46718619: NM_004308 Rho GTPase activating protein 1 46718571 ARHGAP5 chr14: +: 32619665: NM_001173 Rho GTPase activating protein 5 32619772 ARL15 chr5: −: 53603776: NM_019087 ADP-ribosylation factor-like 15 53603718 ARL15 chr5: −: 53212951: NM_019087 ADP-ribosylation factor-like 15 53212826 ARL5B chr10: +: 18963389: NM_178815 ADP-ribosylation factor-like 5B 18963454 ARSJ chr4: −: 114894867: NM_024590 arylsulfatase family, member J 114894796 ASAP1 chr8: −: 131173039: NM_001247996 ArfGAP with SH3 domain, ankyrin 131173031 repeat and PH domain 1 ASAP1 chr8: −: 131135828: NM_001247996 ArfGAP with SH3 domain, ankyrin 131135650 repeat and PH domain 1 ATF6 chr1: +: 161840762: NM_007348 activating transcription factor 6 161840851 BECN1 chr17: −: 40963348: NM_003766 beclin 1, autophagy related 40963310 BHMT2 chr5: +: 78374568: NM_017614 betaine--homocysteine S- 78374655 methyltransferase 2 BIN3 chr8: −: 22501255: NM_018688 bridging integrator 3 22501165 BNC2 chr9: −: 16672136: NM_017637 basonuclin 2 16672064 BTBD10 chr11: −: 13440890: NM_032320 BTB (POZ) domain containing 10 13440824 C10orf76 chr10: −: 103608231: NM_024541 chromosome 10 open reading frame 103608157 76 C11orf30 chr11: +: 76259972: NM_020193 chromosome 11 open reading frame 76260061 30 C11orf73 chr11: +: 86037555: NR_024596 chromosome 11 open reading frame 86037718 73 C12orf4 chr12: −: 4646680: NM_020374 chromosome 12 open reading frame 4 4646546 C1orf27 chr1: +: 186347618: NM_017847 chromosome 1 open reading frame 27 186347702 C1QTNF9B- chr13: +: 24463289: NM_001014442 C1QTNF9B antisense RNA 1 (non- AS1 24463692 protein coding) C2orf47 chr2: +: 200826550: NM_024520 chromosome 2 open reading frame 47 200826651 CACNB1 chr17: −: 37342662: NM_000723 calcium channel, voltage-dependent, 37342603 beta 1 subunit CACNB4 chr2: −: 152728639: NM_000726 calcium channel, voltage-dependent, 152728497 beta 4 subunit CADM2 chr3: +: 85895854: NM_001256504 cell adhesion molecule 2 85895996 CCNL2 chr1: −: 1328183: NM_030937 cyclin L2 1326677 CDH18 chr5: −: 19938439: NM_001291956 cadherin 18, type 2 19938387 CENPI chrX: +: 100411511: NM_006733 centromere protein I 100411544 CEP162 chr6: −: 84932759: NM_014895 centrosomal protein 162 kDa 84932696 CEP170 chr1: −: 243340118: NM_014812 centrosomal protein 170 kDa 243340004 CEP192 chr18: +: 13038514: NM_032142 centrosomal protein 192 kDa 13038578 CEP57 chr11: +: 95527385: NM_001243776 centrosomal protein 57 kDa 95527523 CHEK1 chr11: +: 125526101: NM_001114121 checkpoint kinase 1 125526230 CHRM2 chr7: +: 136686610: NM_001006626 cholinergic receptor, muscarinic 2 136686804 CMAHP chr6: −: 25107418: NR_002174 cytidine monophospho-N- 25107336 acetylneuraminic acid hydroxylase, pseudogene CMSS1 chr3: +: 99770076: NM_032359 NA 99770147 CNOT7 chr8: −: 17101054: NM_013354 CCR4-NOT transcription complex, 17100951 subunit 7 CNRIP1 chr2: −: 68542975: NM_001111101 cannabinoid receptor interacting 68542840 protein 1 CNTN1 chr12: +: 41263098: NM_001843 contactin 1 41263196 COPS7B chr2: +: 232655632: NM_022730 COP9 constitutive photomorphogenic 232655883 homolog subunit 7B (Arabidopsis) CRISPLD2 chr16: +: 84869783: NM_031476 cysteine-rich secretory protein LCCL 84870041 domain containing 2 CRYBG3 chr3: +: 97635177: NM_153605 beta-gamma crystallin domain 97635237 containing 3 CUX1 chr7: +: 101592135: NM_001202543 cut-like homeobox 1 101592250 DAAM1 chr14: +: 59801175: NM_001270520 dishevelled associated activator of 59801315 morphogenesis 1 DCAF17 chr2: +: 172298369: NM_025000 DDB1 and CUL4 associated factor 172298546 17 DCAF17 chr2: +: 172309926: NM_025000 DDB1 and CUL4 associated factor 172309987 17 DCUN1D4 chr4: +: 52775086: NM_001287757 DCN1, defective in cullin 52775141 neddylation 1, domain containing 4 DDX42 chr17: +: 61883354: NM_007372 DEAD (Asp-Glu-Ala-Asp) box 61883511 helicase 42 (“DEAD” disclosed as SEQ ID NO: 3807) DENND1A chr9: −: 126385380: NM_020946 DENN/MADD domain containing 126385322 1A DENND4A chr15: −: 65957563: NM_001144823 DENN/MADD domain containing 65957537 4A DENND5A chr11: −: 9198449: NM_001243254 DENN/MADD domain containing 9198319 5A DENND5A chr11: −: 9227781: NM_015213 DENN/MADD domain containing 9227736 5A DET1 chr15: −: 89087925: NM_017996 de-etiolated homolog 1 (Arabidopsis) 89087842 DET1 chr15: −: 89088400: NM_017996 de-etiolated homolog 1 (Arabidopsis) 89088342 DGKI chr7: −: 137249412: NM_004717 diacylglycerol kinase, iota 137249362 DHFR chr5: −: 79929807: NM_000791 dihydrofolate reductase 79929696 DHFR chr5: −: 79928121: NM_000791 dihydrofolate reductase 79928051 DIAPH3 chr13: −: 60548266: NM_001042517 diaphanous-related formin 3 60548219 DIAPH3 chr13: −: 60266972: NM_001042517 diaphanous-related formin 3 60266851 DLG5 chr10: −: 79572531: NM_004747 discs, large homolog 5 (Drosophila) 79572471 DMXL1 chr5: +: 118508106: NM_005509 Dmx-like 1 118508210 DNAJA4 chr15: +: 78557823: NM_018602 DnaJ (Hsp40) homolog, subfamily A, 78558635 member 4 DNMBP chr10: −: 101762780: NM_015221 dynamin binding protein 101762699 DYRK1A chr21: +: 38794884: NM_101395 dual-specificity tyrosine-(Y)- 38794954 phosphorylation regulated kinase 1A DZIP1L chr3: −: 137783162: NM_173543 DAZ interacting zinc finger protein 137783023 1-like ELMO2 chr20: −: 45023043: NM_133171 engulfment and cell motility 2 45022947 ENAH chr1: −: 225788060: NM_001008493 enabled homolog (Drosophila) 225787910 ENAH chr1: −: 225788064: NM_001008493 enabled homolog (Drosophila) 225787910 ENOX1 chr13: −: 43984398: NM_017993 ecto-NOX disulfide-thiol exchanger 1 43984311 EP300 chr22: +: 41496302: NM_001429 E1A binding protein p300 41496407 ERC1 chr12: +: 1536281: NR_027948 ELKS/RAB6-interacting/CAST 1536343 family member 1 ERC2 chr3: −: 56159162: NM_015576 ELKS/RAB6-interacting/CAST 56159019 family member 2 EVC chr4: +: 5743061: NM_153717 Ellis van Creveld protein 5743168 EXOC3 chr5: +: 466496: NM_007277 exocyst complex component 3 466667 EXOC6B chr2: −: 72410034: NM_015189 exocyst complex component 6B 72410023 FAM162A chr3: +: 122120223: NM_014367 family with sequence similarity 162, 122120382 member A FAM174A chr5: +: 99917051: NM_198507 family with sequence similarity 174, 99917108 member A FAM195B chr17: −: 79781381: NM_001288798 family with sequence similarity 195, 79781288 member B FAM208B chr10: +: 5751493: NM_017782 family with sequence similarity 208, 5751626 member B FAM49B chr8: −: 130937848: NM_016623 family with sequence similarity 49, 130937794 member B FAM69B chr9: +: 139611405: NM_152421 family with sequence similarity 69, 139611665 member B FBN2 chr5: −: 127850450: NM_001999 fibrillin 2 127850370 FBXL16 chr16: −: 746433: NM_153350 F-box and leucine-rich repeat protein 746287 16 FGD4 chr12: +: 32664764: NM_139241 FYVE, RhoGEF and PH domain 32664843 containing 4 FHOD3 chr18: +: 34322340: NM_001281740 formin homology 2 domain 34322431 containing 3 GALC chr14: −: 88447791: NM_001201402 galactosylceramidase 88447758 GBP1 chr1: −: 89530504: NM_002053 guanylate binding protein 1, 89530384 interferon-inducible GLCE chr15: +: 69517534: NM_015554 glucuronic acid epimerase 69517591 GNG12 chr1: −: 68179430: NM_018841 guanine nucleotide binding protein 68179375 (G protein), gamma 12 GOLGB1 chr3: −: 121401810: NM_001256486 golgin B1 121401764 GTSF1 chr12: −: 54862737: NM_144594 gametocyte specific factor 1 54862609 GXYLT1 chr12: −: 42489016: NM_173601 glucoside xylosyltransferase 1 42488953 HDAC5 chr17: −: 42163619: NM_001015053 histone deacetylase 5 42163517 HDX chrX: −: 83756519: NM_001177479 highly divergent homeobox 83756437 HMGXB4 chr22: +: 35663361: NR_027780 HMG box domain containing 4 35663507 HOXB3 chr17: −: 46648520: NM_002146 homeobox B3 46648451 HSD17B4 chr5: +: 118792986: NM_001199291 hydroxy steroid (17-beta) 118793063 dehydrogenase 4 HTT chr4: +: 3215349: NM_002111 huntingtin 3215463 IFT57 chr3: −: 107911373: NM_018010 intraflagellar transport 57 107911323 IKBKAP chr9: −: 111695687: NM_003640 inhibitor of kappa light polypeptide 111695551 gene enhancer in B-cells, kinase complex-associated protein INO80 chr15: −: 41305472: NM_017553 INO80 complex subunit 41305408 INPP4B chr4: −: 143190586: NM_003866 inositol polyphosphate-4- 143190485 phosphatase, type II, 105 kDa INVS chr9: +: 102970748: NM_183245 inversin 102970845 ITCH chr20: +: 32980543: NM_001257137 itchy E3 ubiquitin protein ligase 32980720 homolog (mouse) IVD chr15: +: 40706571: NM_002225 isovaleryl-CoA dehydrogenase 40706723 KDM6A chrX: +: 44965787: NM_001291415 lysine (K)-specific demethylase 6A 44965894 KDSR chr18: −: 61002332: NM_002035 3-ketodihydrosphingosine reductase 61002156 KIAA1524 chr3: −: 108284925: NM_020890 KIAA1524 108284745 KIAA1715 chr2: −: 176835145: NM_030650 KIAA1715 176834927 KIDINS220 chr2: −: 8961232: NM_020738 kinase D-interacting substrate, 8961097 220 kDa KIF21A chr12: −: 39835889: NM_001173464 kinesin family member 21A 39835764 L3MBTL2 chr22: +: 41613520: NM_031488 l(3)mbt-like 2 (Drosophila) 41613848 LGALS3 chr14: +: 55596173: NM_001177388 lectin, galactoside-binding, soluble, 3 55596365 LINCR-0002 chr3: +: 191191340: NR_120606 uncharacterized LincR-0002 191191477 LINGO2 chr9: −: 28080976: NM_001258282 leucine rich repeat and Ig domain 28080822 containing 2 LOC400927 chr22: −: 38766050: NR_002821 TPTE and PTEN homologous 38765991 inositol lipid phosphatase pseudogene LPHN1 chr19: −: 14284211: NM_001008701 adhesion G protein-coupled receptor 14284108 L1 LRRC1 chr6: +: 53784070: NM_018214 leucine rich repeat containing 1 53784138 LRRC42 chr1: +: 54413535: NM_001256409 leucine rich repeat containing 42 54413654 LYRM1 chr16: +: 20922505: NM_001128301 LYR motif containing 1 20922586 MACROD2 chr20: +: 13976991: NM_080676 MACRO domain containing 2 13977165 MANEA chr6: +: 96029731: NM_024641 mannosidase, endo-alpha 96029787 MAPK10 chr4: −: 87168720: NM_002753 mitogen-activated protein kinase 10 87168646 MARCH7 chr2: +: 160619771: NM_022826 membrane-associated ring finger 160619867 (C3HC4) 7 MARCH8 chr10: −: 45955325: NM_001282866 membrane-associated ring finger 45955188 (C3HC4) 8, E3 ubiquitin protein ligase MDN1 chr6: −: 90366293: NM_014611 midasin AAA ATPase 1 90366095 MEAF6 chr1: −: 37959764: NR_073092 MYST/Esa1-associated factor 6 37959741 MEMO1 chr2: −: 32112156: NM_015955 Methylation modifier for class I HLA 32112104 MFN2 chr1: +: 12041867: NM_014874 mitofusin 2 12041910 MLLT10 chr10: +: 22017561: NM_004641 myeloid/lymphoid or mixed-lineage 22017604 leukemia; translocated to, 10 MMS19 chr10: −: 99241240: NM_022362 MMS19 nucleotide excision repair 99241106 homolog (S. cerevisiae) MORF4L1 chr15: +: 79184787: NM_206839 mortality factor 4 like 1 79184819 MRPL39 chr21: −: 26960065: NM_080794 mitochondrial ribosomal protein L39 26960013 MRPL45 chr17: +: 36468550: NM_032351 mitochondrial ribosomal protein L45 36468624 MRPS28 chr8: −: 80915355: NM_014018 mitochondrial ribosomal protein S28 80915234 MTMR3 chr22: +: 30384868: NM_021090 myotubularin related protein 3 30384916 MYB chr6: +: 135520664: NM_001161656 v-myb avian myeloblastosis viral 135520719 oncogene homolog MYCBP2 chr13: −: 77692630: NM_015057 MYC binding protein 2, E3 ubiquitin 77692475 protein ligase MYCBP2 chr13: −: 77628142: NM_015057 MYC binding protein 2, E3 ubiquitin 77628054 protein ligase MYLK chr3: −: 123459382: NM_053025 myosin light chain kinase 123459323 MZT1 chr13: −: 73299916: NM_001071775 mitotic spindle organizing protein 1 73299780 NEDD4 chr15: −: 56132413: NM_006154 neural precursor cell expressed, 56132348 developmentally down-regulated 4 NFASC chr1: +: 204980621: NM_001005388 neurofascin 204980739 NGF chr1: −: 115843104: NM_002506 nerve growth factor (beta 115843018 polypeptide) NIPA1 chr15: −: 23053780: NM_001142275 non imprinted in Prader- 23053689 Willi/Angelman syndrome 1 NLGN1 chr3: +: 173946047: NM_014932 neuroligin 1 173946101 NLN chr5: +: 65118355: NM_020726 neurolysin (metallopeptidase M3 65118497 family) NREP chr5: −: 111086122: NM_001142476 NA 111086049 NSUN4 chr1: +: 46823248: NR_045789 NOP2/Sun domain family, member 4 46823331 NUPL1 chr13: +: 25877240: NM_014089 nucleoporin 58 kDa 25877293 OSBPL3 chr7: −: 24938340: NM_015550 oxysterol binding protein-like 3 24938132 PAPD4 chr5: +: 78937278: NM_001114393 PAP associated domain containing 4 78937340 PBX3 chr9: +: 128726317: NM_006195 pre-B-cell leukemia homeobox 3 128726477 PCDH10 chr4: +: 134074437: NM_032961 protocadherin 10 134074588 PDE3A chr12: +: 20755159: NM_000921 phosphodiesterase 3A, cGMP- 20755255 inhibited PDE7A chr8: −: 66693182: NM_001242318 phosphodiesterase 7A 66693079 PDXDC1 chr16: +: 15103356: NM_001285447 pyridoxal-dependent decarboxylase 15103418 domain containing 1 PDXDC2P chr16: −: 70065151: NR_003610 pyridoxal-dependent decarboxylase 70065089 domain containing 2, pseudogene PELI1 chr2: −: 64339806: NM_020651 pellino E3 ubiquitin protein ligase 1 64339697 PIGN chr18: −: 59764997: NM_176787 phosphatidylinositol glycan anchor 59764914 biosynthesis, class N PITPNB chr22: −: 28290410: NM_012399 phosphatidylinositol transfer protein, 28290364 beta PITPNB chr22: −: 28288318: NM_012399 phosphatidylinositol transfer protein, 28288117 beta PMS1 chr2: +: 190683464: NM_000534 PMS1 homolog 1, mismatch repair 190683555 system component PNISR chr6: −: 99868460: NM_032870 PNN-interacting serine/arginine-rich 99868399 protein POMT2 chr14: −: 77753614: NM_013382 protein-O-mannosyltransferase 2 77753576 PPARG chr3: +: 12427535: NM_138712 peroxisome proliferator-activated 12427591 receptor gamma PPFIBP1 chr12: +: 27769294: NM_003622 PTPRF interacting protein, binding 27769423 protein 1 (liprin beta 1) PRPF31 chr19: +: 54632112: NM_015629 PRP31 pre-mRNA processing factor 54632180 31 homolog (S. cerevisiae) PSMA4 chr15: +: 78834918: NM_001102667 proteasome subunit alpha 4 78834987 PXK chr3: +: 58321084: NM_017771 PX domain containing 58321179 serine/threonine kinase RAB23 chr6: −: 57086244: NM_001278666 RAB23, member RAS oncogene 57086117 family RAB23 chr6: −: 57086244: NM_016277 RAB23, member RAS oncogene 57086141 family RAF1 chr3: −: 12645036: NM_002880 Raf-1 proto-oncogene, 12644977 serine/threonine kinase RAPGEF1 chr9: −: 134479440: NM_005312 Rap guanine nucleotide exchange 134479348 factor (GEF) 1 RASIP1 chr19: −: 49241364: NM_017805 Ras interacting protein 1 49241141 RBBP8 chr18: +: 20557753: NM_002894 retinoblastoma binding protein 8 20557850 RCOR3 chr1: +: 211478332: NM_001136223 REST corepressor 3 211478493 RERE chr1: −: 8456591: NM_012102 arginine-glutamic acid dipeptide (RE) 8456504 repeats RGL1 chr1: +: 183708924: NM_015149 ral guanine nucleotide dissociation 183709042 stimulator-like 1 RNF130 chr5: −: 179390561: NM_018434 ring finger protein 130 179390471 RNF144A chr2: +: 7114066: NM_014746 ring finger protein 144A 7114154 RNF213 chr17: +: 78316103: NM_001256071 ring finger protein 213 78316182 RPF2 chr6: +: 111305510: NM_032194 ribosome production factor 2 111305566 homolog RPS10 chr6: −: 34385674: NM_001204091 ribosomal protein S10 34385575 SAMD4A chr14: +: 55204147: NM_015589 sterile alpha motif domain containing 55204227 4A SCO1 chr17: −: 10594966: NM_004589 SCO1 cytochrome c oxidase 10594907 assembly protein SENP6 chr6: +: 76331643: NM_015571 SUMO1/sentrin specific peptidase 6 76331687 SF3B3 chr16: +: 70561279: NM_012426 splicing factor 3b, subunit 3, 130 kDa 70561332 SGIP1 chr1: +: 67051355: NM_032291 SH3-domain GRB2-like (endophilin) 67051531 interacting protein 1 SGMS1 chr10: −: 52328405: NM_147156 sphingomyelin synthase 1 52328298 SGPL1 chr10: +: 72604233: NM_003901 sphingosine-1-phosphate lyase 1 72604395 SH2B3 chr12: +: 111859705: NM_005475 SH2B adaptor protein 3 111859739 SKP1 chr5: −: 133511076: NM_170679 S-phase kinase-associated protein 1 133510975 SLC12A2 chr5: +: 127478818: NM_001046 solute carrier family 12 127478874 (sodium/potassium/chloride transporters), member 2 SLC25A16 chr10: −: 70250796: NM_152707 solute carrier family 25 70250680 (mitochondrial carrier), member 16 SLC25A17 chr22: −: 41193340: NR_104235 solute carrier family 25 41193288 (mitochondrial carrier; peroxisomal membrane protein, 34 kDa), member 17 SMOX chr20: +: 4133445: NM_175842 spermine oxidase 4133558 SNAP23 chr15: +: 42805372: NM_003825 synaptosomal-associated protein, 42805407 23 kDa SNX24 chr5: +: 122233837: NM_014035 sorting nexin 24 122233931 SNX7 chr1: +: 99204216: NM_015976 sorting nexin 7 99204359 SOCS6 chr18: +: 67981331: NM_004232 suppressor of cytokine signaling 6 67981476 SOGA2 chr18: +: 8828355: NM_015210 NA 8828467 SORCS1 chr10: −: 108337396: NM_001206572 sortilin-related VPS10 domain 108337339 containing receptor 1 SPIDR chr8: +: 48185929: NM_001080394 scaffolding protein involved in DNA 48186042 repair SPRYD7 chr13: −: 50492357: NM_020456 SPRY domain containing 7 50492229 SREK1 chr5: +: 65460436: NM_001270492 splicing regulatory glutamine/lysine- 65460505 rich protein 1 SSBP1 chr7: +: 141441110: NR_046269 single-stranded DNA binding protein 141441259 1, mitochondrial STRADB chr2: +: 202335632: NM_018571 STE20-related kinase adaptor beta 202335834 STXBP4 chr17: +: 53193279: NM_178509 syntaxin binding protein 4 53193304 STXBP6 chr14: −: 25457178: NM_014178 syntaxin binding protein 6 (amisyn) 25457092 STXBP6 chr14: −: 25411028: NM_014178 syntaxin binding protein 6 (amisyn) 25410930 SUPT20H chr13: −: 37585794: NM_001014286 suppressor of Ty 20 homolog (S. cerevisiae) 37585696 TAF2 chr8: −: 120757276: NM_003184 TAF2 RNA polymerase II, TATA 120757121 box binding protein (TBP)-associated factor, 150 kDa TAF2 chr8: −: 120771346: NM_003184 TAF2 RNA polymerase II, TATA 120771264 box binding protein (TBP)-associated factor, 150 kDa TARBP1 chr1: −: 234571617: NM_005646 TAR (HIV-1) RNA binding protein 1 234571386 TASP1 chr20: −: 13395909: NM_017714 taspase, threonine aspartase, 1 13395770 TBCA chr5: −: 77070041: NM_004607 tubulin folding cofactor A 77070009 TBL1XR1 chr3: −: 176865407: NM_024665 transducin (beta)-like 1 X-linked 176865310 receptor 1 TCF4 chr18: −: 53202868: NM_001243226 transcription factor 4 53202790 TEKT4P2 chr21: −: 9963254: NR_038328 tektin 4 pseudogene 2 9963195 TET1 chr10: +: 70440629: NM_030625 tet methylcytosine dioxygenase 1 70440724 TIAM1 chr21: −: 32641011: NM_003253 T-cell lymphoma invasion and 32640727 metastasis I TJAP1 chr6: +: 43453391: NM_001146018 tight junction associated protein 1 43453466 (peripheral) TJP2 chr9: +: 71792959: NM_004817 tight junction protein 2 71793045 TMEM214 chr2: +: 27260130: NM_017727 transmembrane protein 214 27260168 TMX3 chr18: −: 66368055: NM_019022 thioredoxin-related transmembrane 66367951 protein 3 TNRC6A chr16: +: 24769760: NM_014494 trinucleotide repeat containing 6A 24769920 TRAF3 chr14: +: 103356688: NM_145725 TNF receptor-associated factor 3 103356763 TRIM65 chr17: −: 73887957: NM_173547 tripartite motif containing 65 73887894 TSPAN7 chrX: +: 38425575: NM_004615 tetraspanin 7 38425608 TXNL4B chr16: −: 72127025: NM_001142318 thioredoxin-like 4B 72126872 UBE2D3 chr4: −: 103774240: NM_181890 ubiquitin-conjugating enzyme E2D 3 103774195 UBE2L3 chr22: +: 21933070: NR_028436 ubiquitin-conjugating enzyme E2L 3 21933127 UBN2 chr7: +: 138949929: NM_173569 ubinuclein 2 138950208 UNC13B chr9: +: 35291066: NM_006377 unc-13 homolog B (C. elegans) 35291101 URGCP-MRPS24 chr7: −: 43945050: NM_001204871 URGCP-MRPS24 readthrough 43944971 UVRAG chr11: +: 75603173: NM_003369 UV radiation resistance associated 75603437 VDAC2 chr10: +: 76990177: NM_001184783 voltage-dependent anion channel 2 76990208 WDR27 chr6: −: 170061846: NM_182552 WD repeat domain 27 170061799 WDR90 chr16: +: 702156: NM_145294 WD repeat domain 90 702218 WHSC2 chr4: −: 1993796: NM_005663 Wolf-Hirschhom syndrome candidate 1993723 2 WNK1 chr12: +: 1004327: NM_001184985 WNK lysine deficient protein kinase 1004362 1 XRN2 chr20: +: 21326472: NM_012255 5′-3′ exoribonuclease 2 21326525 ZFP82 chr19: −: 36891305: NM_133466 ZFP82 zinc finger protein 36891187 ZMIZ2 chr7: +: 44790571: NM_031449 zinc finger, MIZ-type containing 2 44790690 ZNF138 chr7: +: 64277652: NM_001160183 zinc finger protein 138 64277713 ZNF208 chr19: −: 22168468: NM_007153 zinc finger protein 208 22168407 ZNF212 chr7: +: 148945885: NM_012256 zinc finger protein 212 148945948 ZNF280D chr15: −: 56935772: NM_001288588 zinc finger protein 280D 56935673 ZNF350 chr19: −: 52470649: NM_021632 zinc finger protein 350 52470511 ZNF37BP chr10: −: 43046910: NR_026777 zinc finger protein 37B, pseudogene 43046848 ZNF426 chr19: −: 9645012: NM_024106 zinc finger protein 426 9644915 ZNF618 chr9: +: 116797471: NM_133374 zinc finger protein 618 116797515 ZNF680 chr7: −: 64002295: NM_178558 zinc finger protein 680 64002108 ZNF730 chr19: +: 23321296: NM_001277403 zinc finger protein 730 23321357 ZNF777 chr7: −: 149154134: NM_015694 zinc finger protein 777 149153846 ZNF804A chr2: +: 185677213: NM_194250 zinc finger protein 804A 185677264 ZNF836 chr19: −: 52668638: NM_001102657 zinc finger protein 836 52668509 ZSCAN25 chr7: +: 99216410: NM_145115 zinc finger and SCAN domain 99216516 containing 25
(452) The sequences for iExons produced in certain affected genes at the indicated coordinates from Table 24 are shown in Table 25. In certain instances, detection and analysis of the amount and type of iExon sequences are useful biomarkers produced as a result of contacting a cell with a compound as described herein or administering to a subject in need thereof a compound as described herein.
(453) TABLE-US-00061 TABLE 25 Gene Sequence Gene Sequence SEQ ID NO: ABHD10 GACTCTGGAAGGAAAAACTATATTTCTTTACATTCAGCCTAAAATT 3808 GCATGA ADAL GAGACTTACTGTATGGGTGGACATTATAGAGAAGGAAGAAGTTCAA 3809 GAAGAGCTTAGAG ADAM17 CCTCTGGTAACCACCATTCTGCTGTCTACCTCCACGAGATCCACTT 3810 TTTTAGCTTCCACACATGA ADAM23 TGAATATGGCCACAAGCAGGCTAATAGGGGCCGTGGCCGGCACCAT 3811 TCTGGCCCTGGGGGTGATTTTTGGAGGCACAGGGTGGGGAATAGA ADAM23 CCTGTTTTCTGAAGCGGACGAAGTGCAAATCATATCCAAAGCATAG 3812 A ADAMTS19 TTCATAAATAAAGTGGATGGACAGAATTTCAAGGATCGCATCATTT 3813 CTGACTTCATATCATCGATTTTATAGCCAGAAAGAGCTTTCTAATC TTTCAGCATATTCATGAATTAAATGAGA ADAMTS19 TTTCACCCACCAGTATGTAAGCTGCATGAGGGCAGAGTGAGTTTCT 3814 CCAGCATCTAGCCTAGGGACTGGCACAGA AGPAT4 GATACTGCAGCCATCAGCAGACAATCAATGCAATCATCTCAGACTG 3815 TGTCCTGCGTCCCAGGA AGPS GGCATTAATCTATTCATAAAGATATACGTCCATGACCCAACCACCT 3816 CCCACTAGGGGATCAAATTTCAACATGAGGTCTGGAGGGTTTGGTG TCCAAACTACAGGACTCCTTTAAGAGAGTGAAAGGATAAATCACAG A AKAP8L GTGAAAACAGCTCCAGCGTGAGTTTTGGCACCACACTGGTAGAAAA 3817 CACTTGGTGTTCAGACCCTTTTGGACCTGGGGGAATTGCAGA AKT1 GTGGCCACTTCTTGACTGCTTTGAGTCCCTCATCCGAGCGAAGGGC 3818 GGACGGAGTCCGTTGGTGGGGGTCCGGTTGCCTCTCCCGGGAGCTG TGTAGACTTCTCATACACCAGGGTTCTGGAGGCAGATGGAGGAGCC CTTTCGAAAACAGA ANKRD13C GGAAACCAAGAATACCAACTCACTTTGCCTTGTCTGTGATGAGAAC 3819 TGAAAAACCTACAGA ANXA11 AGTATCTCCTGCATGCCAGCAAGCTATGGACATCTGGAAGAAGCCA 3820 CATGCCTTGCCCTCAAGTTGCTTAGGGTGGAAGGAAATGATTAGAA ATGAGCCAAGCCGAGCCTGCACTCTTAGA AXNA11 CAAGCTATGGACATCTGGAAGAAGCCACATGCCTTGCCCTCAAGTT 3821 GCTTAGGGTGGAAGGAAATGATTAGAAATGAGCCAAGCCGAGCCTG CACTCTTAGA APIP CTCTGAAATTAAATCCCTACTGACTGGCCCTTGAACTGATTTTTTC 3822 TAACATCAGCAAAAGTCAAGGAGTGTTTCCCTAAAAAAGAAAGCAT TTACTCAGAAACCGTATATTGAAGTCCAGGCTGAAAAATGCAAACA TGA APPL2 TAAAATGAAGTTAATGGAACCATGGAATCTACCTTGGAGAGTTGCT 3823 AGAAGAATTAAATGAAGTCACATATGTTTAGTGCCCAGCACAGCGT CCAGCACATAGGTGGTACAGA ARHGAP1 GGCCGTCAACCTTTCCACCTTGAAACTGGTGTCAGGAGCACCCTGC 3824 AGA ARHGAP5 TTCTAGAGGCTGGTAAGTTCAGGGTCAAGGAGGCCTCATCAGGTGA 3825 GGGCCTTTTTGCAAAGTCATTCCATGACCGAAGGTGGAAGGGCAAG AGAGCACACTCAGAGA ARL15 GGAAAAAAAATGCTCCTTTCATTCCAAGTTTGACTCCAGATTTTGC 3826 TGAATGGATTAGA ARL15 GGGCCTTCCAGAGAACAAATGGCTGGTCCTTTTCCAAGGGGACAGA 3827 TTTTCCTACCTGATGCTTTTGTTCTCCAGCAAGAAAAGAAAATGAA AACTGTTGTCTTCCCCTAGAATATTGAGTCCAGA ARL5B GAAGCTTGAAAGAAATTTCACATTTTCTGCAAGGACTTAAACCTGA 3828 GCTCTCAGCTTTCTGCAAGA ARSJ GTAATTAGCTGAGAAGGAAGATCTGAAGGTTTAACGAGAGAGGGCG 3829 AGAGATACAAAATATCTGCTAGGAGA ASAP1 TCTAGGAGA 3830 ASAP1 AGCAAACCCCATTGTCAGGGGAAAGCAGAACAAAGAAAAGTATTTA 3831 GAAATGTATTTCCGGGATGCACAGATTCTTTTCACCCTCACCTTCC CCTAGGTTGTTGCAGCTGCGCACCTGCTCTGTGAAGCACAGATTGT CATGGGGGCAGTTCTCTCAAAAACATGGCATATTGTGATGA ATF6 GTTGTATGCTTTCTCTGTGCAGGGATAAAGTCTATTCATTGTGTTT 3832 TGTCTTTTACAAGATCTATTGCAATGCATTGCAGGCTCGGCAGA BECN1 GATCCCATTGATGGATGGAAACTCTAGTTTTTACTTAGA 3833 BHMT2 GATGTTTTCATCTGGCCCAAGAAGAACTTGTTCTTAATGTTAAAAG 3834 ACCTTTTTGCTAAACTGGGAAGAAAGTGCTGGAATAACAAGA BIN3 AGCTCTCAAAAGTACAGGAAAGAGATTGCTTCAGTGTGGTGAGAAT 3835 TTGGCACACATCTGACCAATGGCTCCATCTCTAGCAAATCCAGA BCN2 GAGTGCCCCAGATCTCCCTGTTTCACCTGTGATTATCTGTGATGCC 3836 ATAGCAACACCCCTTGCTGTTAGCAGA BTBD10 ATGAAAGAACTGAGCTTTGGAGGCTAAATTACTTGTCCCAAGTTAA 3837 TACAGCTTAGAAAGTGATAGA C10orf76 GCAATCTACACAGCTATTTCCTGTGGGGAAATCTCCTTGAAGAGTC 3838 TGCCAGATTCCTCTTGGAACCCTCTCAGA C11orf30 GCCTTGTTCAAAGCTCTGGGCATCTAGCAATGAGTAAGATAGTCAA 3839 GATCTGTGCTCTGTCCACGTTCTCTTGGAGCTTACATTTTAAGA C11orf73 GTAATTATTGAACATCTACTTGCTGCCTACTTTCAACATCTGCATG 3840 TGTGTGTGAATATTAAATATCACACCAAGACATTGTTCAGAGGAGA CAGAATAGTGAGCTGAGATAAATGAGAATCTCTCTATGGAAGATTA GACTGGAGCATGAACTTGAAATATGA C12orf4 TGAGCACCATAAAATAAAAACGCCATACAATCCAACAATTATTTAT 3841 TAGTTCTTGCCATTCGCAACATCCTGCCTAATACATGGAATACAAG ACAGTATTCCTTCCACTTCAAGAAGACTGTTTTCTAGCCAAGA C1orf27 CTATAGAAATGCAAATCAAAGGAGCATAAGCCAATAGAGGGAATGA 3842 ATATACTGACTTCCATCCACAGACCAGAGGGAAAACAGA C1QTNF9B-AS1 GTCCAAGCGGCTGCCCTGGGGCTTGACATTGAAGGCGGCGCCCACG 3843 GGAGACCAGCTGGTGCTGACCCTTCGGGCCCGGATCCCGGCTTCGA GGCTTCCCCGGCCCGCCCGGCGGGGCGGCAGAGCTGCTGCTCTGGC TCCCAAGCCGCCCAGCCTTCCGACGCACAGCATTCTAGCACCAGAG CAGTCCCTTCCTCCAACGCAGATCCCTGCCCTGCTGCTTTCGCTGG GAGCGCGCGCTCCGCGTTTCCAAGGCAGCAGCCCACGCCGCCCCAC GTGACGGCCCCGCTTCCGGGTCTGGGCGCGGCCTCAGGACGTGGGC ACGTTGTCGTCCAGAGAGCAAGAGCGTCGCTCCCCCTCGCCTTCTC GGCCGCCCTCCCGGTTTACCGCCCCCTGTGTCCAGA C2orf47 TGCCAACATCCCCAGTGAAACTTTAAGAGGAGCCAGTGTATTCCAG 3844 GTTAAGTTGGGGAATCAGAATGTGGAAACTAAACAACTTCTTAGTG CAAGCTATGA CACNB1 TAGGAAACACCCCAATCCTGAGTCCCCCAAGCACATGCAGTGGTTC 3845 CCCCTCCATGAAGA CACNB4 GAACGGACAGAGTTTAAGATGGTGAAGGCCAATAAAAAAAGGAAAA 3846 AAATGATGCAGACTCTCAAGAAAATGCTGTTTTCAGTCTCCATGTG GAATTTCAGGATGTATTAGTACAGCCCGAGCTGGAAGGGTTGAAGC AGAGA CADM2 ATTAAAAAAATCAGCCGATGTGGTGGTGCATGCCTGTAGTCCCAGG 3847 TAATTGGGAGGCTGAGGCAGGAGGATTGTTTGAGCCCAGGAGTTCA AGTCTGCAGTGAGCTATGATCATGCCACAGTACTCCAGTCTGCGTG ACAGA CCNL2 GGTAGCCTCTGAGGGTAAGTGACTAAGACTTCTCCTCTGCTGTCCA 3848 AGCGCTTTGGTGCAGGGACAGCGGCATCTTCAGCCAATCCAGTGCA GGCTCTCCACCGAAGGCTGGCTCTAGACTGGTGGTACGCACATAGC ATAGCCATGGCCGACTCCTGCTGTGGTTCTCTGACGATTGTGCTTC TTGTTAATCCTCTGTCGTGCTTTGGTAATCGTATTGATTAGAGTTG GTAACTGTCTTGACTTGAATTTTGTCCCTTTAAAACTGCTGTACCT GTATGATAAAGATGCAGTACCTTTCTCTTAAAAAAAAATGCTATGG AAAGCTGTGAGAATTGAAGAGACAAATTGGCTGTGTCAGTGTGGGG TTATGTCATGATTTCTAGAAGCCCTGAAGTTGCTCTTTTGAGCAGC TTTGCATGACACGCTCTGGTAAAAGGTGTGCATCTTTAAATTATTT CATGGATACTTTGAAAAATATTGTATCACTTCAAATACAGCAATAA GTTTATATGTTCTCAAGATTTCATTTGTTTTTAAGAATTTTAAGTT CGTGGATTAATATCACTACTTGAATACTGACAGTTGTTGATTAGAC ACCGAAAGGTTACTGATTGTTGAATGTATCTGTGTTAGAGCTGTGC ACTGGCACGCTTGCATCAGGGGCTGGGGCCACACGGCCGCCACACA GATTCCCCCGTGATGCCTGGAGCTGCTTCCAGAGCCGGGTGTCTCC AAGAGGCACCTGTAGGACTTCCCATTTAGAAATCTCTTGAGTGGGT TTGTATGTTACCTTCTCCAAGGTTTATTTAGGACAGAGATATTGCT GGAAGGTCATGGGTCAGATTCCCTCACAACCCACCTCGTCTGCGGG TGCAGCCCCACTCCAAGGCTCCCCGTTATTGGGGTATGTGAGGAGC AGTAAATATAAAACCAGTTCAACTGTCCTCATGGAATCACCCTTTC TGTTTTTGCAGTATTCATAAAGCTAGTGTAAGGTCTGGTTTTAGTC TATTAAATCTTAGAGATCTAAAGGAAATGCTCAAAATGTAGCCAGG TTTTAAATGCTTTAACTTTTAAAAAATGTAAATTTTTGTATGTTTA TAGCTTCTAAATATGAAAGTTAAAGAATGTACTGTGATGAAATGTT CAGTATTATGTTGCTTCTCAGTATCATGTTGCTTCTCAGTATTGTG TTGCTTCTGATTCTATGAATGTTCATTTTAAGACCCCTTGTTGAAA TGGGACAGTTGGCAGCGGCTCTGATGAGCCCGAGAAGAGGCCTGCC CTTGGGTGCGGAGTCTCCCTCCGCACGATGCTCCCACGCGTCCAAC TTGCACCCAAGGGGCTTTTCCCTCTTCCAAGTGGACTCCTTCAAGG AAGCTGCAGCTCGGTCAGCAGAGAAGGGGCCTGCCGCCAGCGCCCT GGAGGAAGAGGAAGAGGAACCCAAGAGGATGGCTTGTCTCCCAGCA GCCACACCGGCTTTGTGCTCAGCCAGTTCATTTGA CDH18 TCAGGAAGTCTGAAGTCTAAAGGATATGAGCAGAAGTTAACCATGA 3849 CAATAGA CENPI GTTTTTGGGGAACAGGTGCTATTTGGTTACATGA 3850 CEP162 ATAAATTGAAAAAATGGGAGGAAAGAGAAATGGAACACCTCAAGGT 3851 GATACTGAAGTTTAGAGA CEP170 GTGACAGCCTCTTCTTTTTATAAGCTCCTTTATCAGACGTAACCTC 3852 CTCAAAAGCAAAGACTGTCATACAGATTTTGTAATCCCCTGCAGTG GCTAGCCAAGTAGCCTGTGGAGA CEP192 GAGAGTTCTTTGCTCAAAGATCTGAAGCTCTTGGTTGCCTTGGTGG 3853 TGGTAACAATGTGAAAAGA CEP57 ACCAGAGGCTGGGCTCTGGATTACAGCTCAGTAGTGGGTCATGGAA 3854 TATGTACTGTGACTCAACCCGTATCATTTTCAAGAAAGAAGAGAGA GAAAATCGTTCAGCAAATATAACTGAATGAATTATCTGGTTCACAG A CHEK1 GTTGAGGCCTTGGCTCCTGCCTGTAGTCCCAGCTACTTAGGAGGCT 3855 GAGAGAGGAGGATCGCGTGAACCTGGAAGTTTGAGGCTGTAGTGAG CTATGATTGCACCAGTCACTCCAGCTTGGATGACAGA CHRM2 CCAGTCTCAGCAGAAGAGTAACATGACATGAGAGATTGGGAAACTG 3856 TCCTTCTGTGGGGTTCTTCAGACAACCTAAGCCATCTCCTACATCC TACACTCGCTGAACATAGAATGGTTGAAGGAAAGAATGAATACATA TGTAGAAGAGAAGAATCTTGCTAAAAGGAATGAAGTTGTCAAGATA AATAATTAAGA CMAHP AATGAACACTCCATGAGAGCAGGGACCTGCTTTGCCTTGTTCACCA 3857 CTTTATTCCCAGTGGCTAGAACCACGTCTGACACAGA CMSS1 GTTTTTAAAACTCATTTGGACACCCACCTCAATATATGCTGTGCAA 3858 TTAGAATAATCCAGAAGACTGAAAGA CNOT7 TTCTTCAAGAAACTTGGTTTTAGCATTGGAATACTGTGAGCATCAT 3859 TTCATGTATCCTTTGGGAGACAGGAATTTATGATTTTCCCCCCTTT CTTGGTTATAGA CNRIP1 TTAACCGGGTGTGGTGATACCACACCTGTAGTGCCAGCAACTTGGG 3860 AGGCTGAGGCAGGAGGATCACTTGGATCCAGGAGGTTGAGGCTGCA GTGAGCTATGATCACACCACTCACTCCAGCCTCGGTGACAAGA CNTN1 GGTCTTTGTCACCCAGGCTGGAGTGCAGTGGAGCTATCACAGCCCA 3861 CTACAGCCTTGCCCTCCCTGGGATCAAGTGATCCTCCCAACTCAGT CGCCAGA COPS7B TAGAGACGGGGTTTCACCTTGTTAGCCAGGATGGTCTCGATCTCCT 3862 GACCTCATGATCCACCCGCCTCGGCCTCCCAAAGTGCTGGGATTAC AGGCGTGAGCCACCGCGCCCGGCCCACGTTTGTGATTTAAACAACA ACAACAACAACAACAACCAGTTAACGTAATTGACAGCAGAGAAGTT CCAGGCAGAACAGTGGCTCTTTCGTTTTTCTTCTACACATGGCTTT TTGCCATCAGCATCAGTGAAGA CRISPLD2 ATTGGGTCTTATCCCCAAGATATCTCATTATGTACATGCAAATCAG 3863 CGGAGCATCGTCATGACACCAGGAGGACACCCCGTGACGCCGATTA CCGCACTCTCAACCTCAACCCAGCGTCAGAGTTTTCTGGCATCTCT TCTTTGAGCCTGGCCGCCTGCAGCTGGAAATGCTCATATATGGTGG TGTGACTAACCTGAGAGAGAGATCAGGGATCCTGAGAAGTTCTGCA TTCTTGGTCTGCTTCCCAGTGGGACGA CRTBG3 GGCCTTTCTGTCTGGTGTGTGCAGAATGATCTGGGTCACCTCTGAG 3864 GCCCATATTTATAGA CUX1 CAGAGAAATCTCAGGAGGCACCATGCCAGGCCACTGTGCCCCTGCA 3865 AGTGTGTCTGAGTATGGCCCAGGACCCTGCCCATCACTGGTCTGCA ACAAGATAAGCACAGAAGTTCAGA DAAM1 AGTCATGACACCCTGTTCAAACTCTCTGGACTTCAGCCAGTTGTTT 3866 GGCTAGATACAATTCTCAGAGAGGCAAAGGAACATTACAAAGGTAA TGGCATGAATACCATTACCTGTATGCATGCAACAGGAACCCTGCAC AGA DCAF17 TTTTGCCAAGGAGTTTGTCCACAGAGCTCTTCATGCCCTCATGCTG 3867 GAAGTGGAAATCTGGACATGTTATCTTATCATGTCATTATCACACC TAGGAAAATGAGCAACAATTCTTCAGGATCATTTAATGTCAAGTTT ATAACTTCCTGCTTTAACTTAAAAAAAAAATTAAATTAGA DCAF17 GTGGATCATATTGGATACCTGTGGTCATTAACAAACTACTATGTTA 3868 TGAAATTACAAAATGA DCUN1D4 GCCGAAGATGGTGTTAGTGATTGCGAGCTGCTGGCTGGCACCCTTG 3869 CAGAGCAGGA DDX42 GTGCAGTTTGAACAGGGCTTGACAGTGGCTGGACCATCACTAAGTG 3870 AGACTTTAATTCATCAAGCATAACTGAAAATGGAGGCAGTAGATTA TATCTTGGTAGCCAGCATGTGTAGACTTGTCTTATTTGGAGCCCAC TTGGAATTTTCATTTCAAGA DENND1A CTGTGGCATAAGAATGAAAAGAAAAGAAACAAAAGCAGATGGCAGA 3871 GAAAACGAAAGGA DENND4A GTCAAAGTCGTACTCTTTTGTTTGAGA 3872 DENND5A GCCAAAATCATATTATATGATCAACCTCAAGTGCATGGGAAGCTGT 3873 GAAAGTGAACATTGAACTGGGTATAATGTTACCCTGAACAGTATGA AGGTCTATGAGCAAGAAAGAAGGGGTGAATGAATTATGA DENND5A ATAGGACAGCATTTAAAAATCTCATGTGGAAGAATATACCACTAGA 3874 DET1 GAGTGATGAATCTAAGCAGGAATGCCATCCACCTTCAGAGCCATTG 3875 GCGTGAGGATGACGGTGTGAAGTCTTTTCAAAGCAGGA DET1 TACATAATTTAGGATGAGAAGCACGAGTTACCGAATGAAGATCTGG 3876 TTGATCCCCCAGA DGKI ATAAAATTCTGGAACAGACAATTATGTCCTTACAAACAACAACATT 3877 TGAGA DHFR CCATGAATCACCCAGGCCATCTTAAACTATTTGTGACAAGGATCAT 3878 GCAAGACTTTGAAAGTGACACGTTTTTTCCAGAAATTGATTTGGAG AAATATAAACTTCTGCCAGA DHFR GCATGTACTAACATAACATCATAACAGCCTCTTTAATGGAATGGAG 3879 GGAATTCTCTAACGGGAGACCTAGA DIAPH3 GGTTTTGTTCCTAATGTCACATGTTTCCTAAGTAATTCAGCATAAA 3880 GA DIAPH3 GTAAATTAGACCCAAAATAACTCCCAGGGAGCAATACACAGCCTGG 3881 AAAACATGAAACAAGGAGCGGCTGTTTGGTGTAATAAAGGAGGAGC ACCAGGCTGAATTTTCAGAGGCCTAATAGA DLG5 GATGGAATGTCATCCCAGGAGCCATCTCTTTTCCTCGGAGGGCATC 3882 TCAAGACCCCCCAGA DMXL1 GATAGGCAGTACTTTGTGAACCAGCTACAACAGAATCAGCTGCAGT 3883 GCTTGTTAAAAGTCTGGATTCTCAAGTTCACTCCAAACTTATTCAA TCAGTTTGTGAGA DNAJA4 GGACACGGACATCTGCAACCTGACATCAGCTTGTACTCATATTCTG 3884 GGTTTTCGGTGACAAGTGACACACAGTTGATCATAAGTACCAATCA TAGACTGAAAATGCTCTGCATTTTAGAGACAGAAGTTAAAAGCTTT TCCATCCTGTTTACAGAAAGTTTGCTTTTTATCTCTAAAGAGGCTC ATGACCCACCTGAATAGGTGAATTGAAGGATGAGGCATTGCAAGGA AAGGCTGCTAACCCTCCCGTTCCTCCTTTCACTTCTTGCCATTTTC TTACAAAACTTTGGTTGTTCCGCATGGGTCTTGAGAGGTGGGGCCG TTATAGTAGCTGATAGCAGTGTCACTTGGGCCACGTTTGAAACCAC ACCAATCACCCATGTAGCATTTAAGACCTGTGGAAACGACGCTGGA ATCAAAATACCTGTCTGTGTTAGTTGTTCCAAGCTGGAGAAAGCTA CTTCAGGACGGTTGGCTGAATGGCAACAGTGATGGAATATTTATAT TTAGCCACATGTGCTGAATGTGGCTGTCACAAGTTTAAAATGCTTT CCTGTAAGACCATTTGTCTGTTACTCACTTGCGTTCTTTCTCATCT ATATTTAGATGGCTTACTGTAGCTTTTAAAGGCACTGGCGTTTTAC ATGGTGCTGGTGATTCATCCACCTGCTCCCTACATTCATTGTGGTC CGCTTCTGACAGTCTCCTTTAAGGAGAGCTTGTAGGCTTCTAATTT CACATTTCAGCAAGCTGGCTAAAGACATGTGGGAAAGCCTGACCCT GGATTCAGGTCAAAATCTCAGCACTCACAAGA DNMBP CATTGGCCAGGACTACTAGAACTGTGTCAAAACAGCTGCTACACTA 3885 ACGGGCATCTTTGTCTTGTTCTCAGTCTTAAAAAGA DYRK1A GTTCAGGGATGCTGGAAAGGACACTGAAGTAGGCCTTGGCTGATGG 3886 GCCTTTCAGAAGTGAACACTTAAGA DZIP1L CAGCTGCTCTTCCAGCCCGGTCTCATCCCACAGTGGGCTCCTCCCC 3887 AGTCCCTCACTCTGCCATGGACCCTAACACAATATGTGTGTGGAGC GGACTCCCCCAAGGGTGGTACTGGAGTGGCCTCGCATAGCACATCA GA ELMO2 GTATGCTCCTGAAGTGAGAAGCAGTGGTTCAAGGAAAGGCACCTGG 3888 GGAGTGCATGGCAGAGGACATCTTGAGGGATGGGGACCACCGGCAT CAAGA ENAH AGTCTGACTGTTGCCCAGGCTGGAGTGCAATGGCACCAACATGGCT 3889 CACTGCAACCTTGACCTCCTGGGCTCAAGTGATCCTCCCGGCCTCC GTCTCCCGAATAGCGGTCTTACTCATTTTCTACGTGTGTGTTGAGT GCACCATTTGAGA ENAH ACAGAGTCTGACTGTTGCCCAGGCTGGAGTGCAATGGCACCAACAT 3890 GGCTCACTGCAACCTTGACCTCCTGGGCTCAAGTGATCCTCCCGGC CTCCGTCTCCCGAATAGCGGTCTTACTCATTTTCTACGTGTGTGTT GAGTGCACCATTTGAGA ENOX1 CTGCCTAATTGAAATATTCAGAGACAGAAGTTACTTACTCTCGTCT 3891 CACCTCCTACTTCTCTCAGAAAATGTAGTACGACTTCTAGA EP300 GTGTTTGAAATGGCAGAAAATGAAACGGGGTAAGGATGAACTCCTG 3892 TATAGATAGACTGGATAAAGAGAAAGCCAAGTGCATGATGTTCATA GAGGAGTCTTAAGA ERC1 ACAGACCCTTCCAGAACCAGATGACCATCAAGACAAAAGCATACTC 3893 AAGCAGACAAGAAAGGA ERC2 GCTGAAGCAGATTCAATATGGACTTGTTAAAACGTATGTTTTGTAA 3894 ATTGAGTTTATCTAAATCCCAGTCTAGAAGAAGGAAGCTCATTTTC TCTAGAAAGTGAATTTCAAAGTAAAACCACATGTTGGATGAAATAC AATAGA EVC TTCCATACAACTATCCCGCTGATTCTTTCTTCAAAGAAGCAAACCC 3895 TCCTTTGCTTTTTATATTTTCTTCACACATGGAAATGGGGGATGTG GAGGGCCTTGCACAGA EXOC3 GGGCCACCTCCATGGCTGCAGCCGCGTCACCTCCGTCCCATCATCT 3896 CGCTGGTTAAACGTGGAAAAACGGGGTCTTGAGCTCTCCACGGTCT CCCCTCTGGTTGGGCCGGAACAAAGATTTATAAAAGCAGTGTTGAA AAATCTTTCTGCAATTGGATTGAGAAAAGACAGA EXOC6B GATATCTAGAGA 3897 FAM162A GTTGGTTCATGTGATCCTGGTTAATGGAACATAAGTGAGATTTTAT 3898 GGGTGACAGGGAGAGAGATCAGGCTTGACTTGAGAGCACGTGGGAA AAGAAGGGGGCTATCTCTTCGCAAAGATTTAAGTATCTTATAAGAA CTGTTTGCCAGTGCAATTATGA FAM174A ACTGCTGTGGAATTCCTGAGAAAGAGCAACTGAGGGATAGCAACAT 3899 GGATTTCACTGA FAM195B GGTGTGGAGCGAGACCTGCGAGGCCAGGTGCCGGGTGGCGAGCGGG 3900 GCCTGGTGGAGGAGTATGTGGAGAAGGTCCCTAACCCCAGCCTGAA GA FAM208B CATTTATGACATTAACAGAGAACAGGACTATGTCAAGAATTCTGAG 3901 GGTATACTTGGTGAAAATGAATTAAGACCACCCTCCCAGCTACATT CTCTCTTAGAGAAGATCGAGACAGGGTCCCTATCAGAAAAGA FAM49B ATCACATGAGGGCCACCTGAGAGAAGTGAGACCACATGAGGGAAAA 3902 CCCAAAAGA FAM69B GCACAGTGGCTCACACCTGTAATCCCAGCACTTTGGGAGGCCAAGG 3903 CAGGTAGATCACCTGAGGTCCGGAGTTCAAGACCAGCCTAGTCAAC ATGGTGAAACCCCGTCTCTACTAAAAATACAAAAATTAGCTGGTCG TGGTGGTGCATGCCTGTAGTCCCAGTTACTCGGGAGGCTGACGCAG GAGAATCACTTGAACCCGGGAGGCAGAGGTTGCAGTGAGCCGAGAT CGCGCCACTGCACTCCAGCCTGGGCTACAGA FBN2 GATTAATTACCGTTAATGTCTTGGAGACTATAACGTACACTGCACG 3904 TTGTAATAACACAAAAGGACAAGCAAGATGTAAGA FBXL16 AAATTAGCCAGGCCTGGTGGTGGGCACCTGTAGTCCCAGCTACTTG 3905 GGAGGACACTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCGGGGG GTACAGTGAGCTGAGATCATGCCACTGCACTCCAGCCTGGGACCTG GGCAACAGA FGD4 AAAAAGACAGTCTACAGCCATACCACCCGGAATGTGCTCAATCTCA 3906 TCTAATCTCAGAAAAAGACAAATTTCCACGAAGA FHOD3 GACAAAAAGCAAAGAAGAAGACTGTGGTCTAGAAGCCGAAGGAAGA 3907 TGAGAAGGAAGAGTGTCCGAGGAGTCAGCCACAGCCAGAAAGGAGA GALC GTTTTTGGAGAATAGGTGGTATTTGGTTACATGA 3908 GBP1 GGATATGATTACATTTCCATCGTCAGTGATGGACTGAATCCTGCTT 3909 CTATGCAGCTAAGAAATGGAAGAGTTACAAACGGGTTCTTTTCATG GAAGGAAAGAACAGCAAATGAGAAGCAGA GLCE GGCAGAGGTGGAGAGGGGTTAGATTATTTCATCTGCCCTACAGTTG 3910 GCATAATAAAGA GNG12 AAGAGGCAGATAAAGAGCTAGAGAAAGACATTGAAAGTTGAAGGCA 3911 AGACCAGAGA GOLGB1 AGGTGCCTGATGCTGTTAATTCCTGAGCCTTTTGAAGATTCTGCAG 3912 A GTSF1 CCACATTTTTTTTTTCTTAAATATCACCTGGGAGTGTGTTGGAAAT 3913 GGACAATCTCAGCGCTCATCCCAGACCTACTGAATCAGAATCAGCA CTTTAACACAGTCCCTAAGTGATGTAACACCTGGAGA GXYLT1 GGATTGTTTGTATTCCTGCCAATGATTTGTGAGACAGTCTGTTCCC 3914 CACATCCTCGTCAACAGA HDAC5 GTCTGGGATGAGACCAGAGTCCTCTTCCCTATGAAGCTGCCACAGG 3915 CTGGGCTCTGGGGGGACACAGACGTGCCTGAGGGTGGCCCTGTATC ACCCGTGGAGA HDX GAGCTCTGATTTGAGGTGACAATGATTTTGAACCTTAAATTCTTTG 3916 GAAAGACTCAGAATGAAGTCCATTGTGGAGGCTCAGA HMGXB4 AATTTCCAGTCTAGTGACGTGATAATGCCATGGACTAATCATCCAG 3917 TGCTGAATGTCGGAGCACAGGGTCAGGGAAAGCTTGAAGAAGGAGA AGGTTTCAGTGGAAGTGGACGCATGGAGGCAGAGAGATGTTCAGGA AGCAGCAGA HOXB3 CAAGAAAGTGCTCGGCTCGCGATCAGGCGCTTGTTTATTTGAACGT 3918 GGACATTCCCAGGATCCGAAAAGA HSD17B4 CTTTCTGACATCTTAACGAGGCAATACAGAGAGACGAATTTTCATC 3919 AGTTTGTTCAGGGAGACACATATAACAAAAGA HTT AGGCAAGCCCTGGTGCTGTGGGAGCCCCAAGGAAGAGCCTCTGGCC 3920 TGGTGGCCACGTAGCCCAGGAGAGATTTCTACAGGAGCCCACAGCG CTGAAGGAGAGAGAGGCAGCAGA IFT57 ATCCATACATACTTAATGCTGAAATGTGAAGGGCTGAGAAAAAAGA 3921 AAAGA IKBKAP TGGCTGAGTAATCTTCAGATCCCAGTACTTAGCAAGTGCTCAGTCG 3922 GTGTTGGATGTAGGCCACAAACCGGATCGTAAAGAATTCAACTGTA TATTGACAGCCACGGAACTAATCAATGAATAGATCCGTATGAAGA INO80 GATTTTCCTTTTTCTCTTGAAATCGTATACCCTCTTCAAAGAGAGA 3923 AAGAAATGCTTCCAATAGA INPP4B GTTGAGGCTGCACCTGGGAAAAAACACAAATTAGAGGAGCATCTGT 3924 GACCCCTGCCTTTTCCAAAGAGGGTTTTGAGGACTCCGATATGTAA AAGAGAAAGA INVS AAATCCCATCCATAGTGTGGAACTGAAGTAGAGAAGGCAAAAGATG 3925 GATTCAATCAGTTGTTTGAAACAGGTCCCCCAAAGGCACACATCTT CGCAGA ITCH GGTCTTCCTCTGTTGCCCAGGCTGGAGTACAGTGGTGTGATCATAG 3926 CTCACTGCAGACTTGACCTCCTGGTTGGGGAGTGGTGGTGTGCACC AGTGGTCCCAGCTACTCAGGAGGCTGAAGCAGAAGGACCCCCCCAG CCCGGGAGGCGCTCCAGAACACCCCAGCTTGGGTGACAGA IVD GCCATCCAGTCTCCTGGCTTTACTGGGTGGAGAGGTGCTCAGCAGC 3927 TTCTGTCACTAGCTCTGAATGGCCTGTCTCCTGGACAAAGAAGCTT TCACGGACTACTCTGCAGGGAGGTGACATTGGACCAGAGCTGACTC CACCTGGGGGAAAGA KDM6A GATATTTTCATTGTCTCCGAATTTTAGAGCTGAAAAGTGCCTTAGA 3928 GATCATCTAGTTCAACCTCTCCGTTCAAATGGAGAACCTGAGCCAC TAAGATTCACAGGAGA KDSR GAATGAGTAAATAGGTTAAAGATATAACTTCAGGAATTTAGAATGG 3929 CAAGAAGTCTTCAGTGCCGGGCCTTGCAGATAGAGAAATAAAACAC CGTATCTGCTGTTGAGGTGTTAACCTGGATTTTCACCTAAGAACCA CTGCTCCAATGTGTTTTGAAAATGGAATACTCCTCTAGA KIAA1524 GTCAGGAATTATGGTTAAAGGTGGATTTTCACTGATGGTAATAAGA 3930 TATTACTTTATACCCCTTCCCTCCTCATGAATTAAGTCCATCTAAT CTTTACTGAGGACCTGCTGAGTGGTAGACACTATGATTTGTTTCTG TTTCCACAGATGTCACAATTGTCAGTAATTGTGGACCTTTAGA KIAA1715 TTCTCAGGTTTTCTTGACACCAAGAAAGAGAGGGAATCAAGAAGAT 3931 CGGTTGTAAGAGAGCAATTCAACATGAAAATACTGAAGAAGAGATG GGAGAGAGAGAGAGATAATTGTTTTCTTCAGAGTTTTCCACTTTCT ATCAGTAACTCTGATCACATGGATATCTATTGTGGGGCTAGTTGAT GCATCCCTTCAGATGTGTTGGAAAGAGGACCAAGA KIDINS220 AAACACTTACCTATGTGAACATCTGAAATGTAACTGTGACCCAGAG 3932 CGTAAACAGAAAACTTCCCTGAGTCTTTGGAATTATAATTTTGAAA ACTGTGATGTAAAATTGATGTATTCTCAGGACTGTGGATTTAGA KIF21A GCACGAGTATTCGATGTAATTTCGGCTGTTTTGATACTTATCAAGA 3933 AGGAAAGCTCTGATAGTTGCTCATGGAAAATTGCAACATCATCACA CTGTGTGAAAAATTAATGAAGCATTCATCCTAGA L3MBTL2 CATTTTCCCATGGAAAGCAGGGTGCTTCTGTAGCTGGCCTGGGCCC 3934 CGTGGGCCCCGAGAGGCAGATGTGGATGCTCCTGGAGCCACTTCTG TAAAAGGCTCCTCGATGCGGATCATGTAAAAGCCAGAACGAAGGGC AAGGCCCTTAGGGGCGGGGCTTGAGCGCAAGAACCGAATATCCAGC AGCTGTGACGTGTGGAGCCTGCAGGCCGGGAGAGCAGAGCCCACAA CAGCACTCTTGTTTTGTCTTCACACCACGTCCCTAAGCTCCGGGAA ATCCAGGAGGAGGCCTCTTTAGTCTTGAGGAAGTAGGGAGTCTTTT ACCCAGA LGALS3 GAGCGGGGCGGCGGGCAGCGATCTGGGCCCGGGGCAGTCGCCTTTG 3935 ATTATCGAGGGCGCTGGCGTTCGGGGAAGGTTGGCAGCACCTTACG AGACCCACACACGTCCCCGGGGCGGCACGGGCCACCTTCTGCGGAG CCTCGTGGGCTTCGCCGCCGTCGCACCTCCGCCGCCTGCGCTCTGC GGCCCCAGA LINCR-0002 AAGTGGGAACAGAGGCTATGGTAGTAGTTTACTTGTCCAAAGACTC 3936 AGAGCTAGTGACTGATGAAGTTGGGACTCAAATCCTACATTCTACC TCTTAAACCAGGAAACTTCCCTCTACACCCCACTGCTTCTGAAGA LINGO2 GCTACCTTCTCCTGCCACAGATACTCTATCCCATTTGCTGTCATCC 3937 AACGACTAACACCGTTTTCACTTCAGAACGTCAAGCCTTTTCTGTT CTCTTCATGGCCTCCTCCCATTAAAGCTGAAAGTATCTGCTATCAG TCATTTGTCCTAACTGA LOC400927 AATGTTAGAACGACTTTCCAAGTTTGAAGTTGGAGATGCTGAAAAT 3938 GTTGCTTCATATGA LPHN1 GCACAGCTAGATGCGGTGGCTCATGCCTGTAATCCCAGCACTTCGG 3939 GAAGTCGAGACTACAATGAGCCATGATCACACCGCTGCTCTCCGTC CTGGGCAATAGA LRRC1 GTTCTAATGGGAGAAGTGAGAGCAGAAAAGGGAAGCACAGGAACCT 3940 ACTGAGGAATCCACTTGCAAAGA LRRC42 GTTGATGTCATATTTTTAGTCTTGAGAAACAGCATCATGCCAAGGA 3941 AAGAGCTTGAGCTTTGGAGTAATGCGGCCCTGAGATTGAATTCTGG CTCTGCCACTTATTAGCTCTGTTCTAGA LYRM1 GTGAAGTAGTATTTGAAGCTTTTCATCAGTTGGCTCATTCTTTACT 3942 CAAGAATAAACCTCAAGAAACGTCATCAGGGTCAGA MACROD2 GTTTCCTTCCTTCGCTGCCGCAGCGTGACTTTTGAAACCTGGAACT 3943 CTAGGGGAGCCCTAAAACGAGCGTGTTGTCCGTGAGGATAAGTGCC TTCAGAGAAGTCTGAATGGGCTGTTCTCCCAACAGTGTGTTTCTCT GTATTCCATCCCCATTCATGGGCTGAAGTTGCTCAGA MANEA AATACCTATCCAAATGTTTTCCTTCTGAAGTATTATGTTCTACTTT 3944 TAGAAAACAGA MAPK10 ACCTTAATTCTATGAGAGTAGGGGCTGTGACTCATTTATCTGACTA 3945 AATCATGGCCTAACGATGCCTCAGACAGA MARCH7 AATTGGAAACATCGAGGGAAAATGGGCTTTTTATTATTAAAACAAA 3946 ACCTCAGTATTATCACTTAGAAACCTGAAATTGAACTCCAAAAGCC AAAGA MARCH8 TAAATGAAAAAGAAAGTCTGGCTATTTGGAGTAAATTAATGAGCTC 3947 CTAGAGGAGATGGGACTAGCAGAGTCTGCTTGTACCAGGAACTCTT AGCGTCGATTTCGAGCTGTTGCTGCCAAAGTAGCAAGGACCAAAGA MDN1 ATATGATAGCAGCCTTGGTGAGCAGACCACGACCATGGGGTTTACC 3948 CAGTGGGATCCCGTCACGGCTTCTTCCCTGCCTGTGTCTCTCCCCG ACCCCTGATTCCGGCCATGAAGTCTTAAGAGCCAAGTGCTGTGTGC GGCTGCCCAGCACAAACCGTCTCACTCTTTTCATTGTCCATAGGCT TTTGCTTTTTTAAGA MEAF6 GGTCAAACAACTGTTCTGCCGAGA 3949 MEMO1 AAAGCGTGCTCTGGAATGGATTCACAAATGAGCTACCCTCCTTCCC 3950 TCAAAGA MFN2 GGCACTTCCTCACATGCCAGCGCAACTCCCCAATACCTCAATGA 3951 MLLT10 GAACCCTCCCTCAAGCATGGTGTTAGACTGGGTGACAATGGAGA 3952 MMS19 CATTAATTTACAGAAATACACGTATTCTCCTTGTTTTGGTGGAAGC 3953 TGCAGCTGCCAATCATCTCTCAAACCCTGTGGGTAGCTGCTAAGCT GTATTTCAGAGGAATGTCACAATCATACCACTGGGGAGAAAGA MORF4L1 AGGCTGAACACTTTAGAACTACTACCAGAAAGA 3954 MRPL39 TCATTCTTCACTACCTCGCCTGAGTCGTACCTCCTCCATGGAACAG 3955 TCTCAGA MRPL45 GTCTGGGTGGTGGCTCATACCCGTAATCCAGCACTTTTGGAGGCCG 3956 AAGTGGGAGGATTGTTTCTGGGCAGCAGA MRPS28 ATGGGACCTGCAAAGGATAAACTGGTCATTGGACGGATCTTTCATA 3957 TTGTGGAGAATGATCTGTACATAGATTTTGGTGGAAAGTTTCATTG TGTATGTAGAAGACCAGAAGTGGATGGAGA MTMR3 AGGCGTGTGTGTATGTGTGTGTGTTTCTTTTCCTGAACAGATTGAG 3958 A MYB ATAGGACCTCTTCTGACATCCCCAGGAATATTATATGATTAGAAGC 3959 CAAGGGATGA MYCBP2 GTGACCAACTGAGTGCCATATTGAATTCCATTCAGTCACGACCCAA 3960 TCTCCCAGCTCCTTCCATCTTTGATCAAGCTGCAAAACCTCCCTCT TCCCTAGTACACAGCCCATTTGTGTTCGGACAGCCCCTTTCCTTCC AGCAGCCTCAGCTTCAGA MYCBP2 GCATCTAGCATAGAACTCCCTATTCTGCATTATGACTACTGGACCA 3961 CTTATCTCTCTGCCCTACTTGATAAGTTCCATGAGGACAAAGA MYLK CTTGCTGCTACTTGCCAGGCCTTAAGTGGAAGAATGGAGTGTTGAT 3962 TGTGTCAGTCAAGA MZT1 GATCCCATTTGAACAGAAAACTCACATTTTCTCTGGTGGAATCACT 3963 GATGTACAATTGAGAACTGATGGTTTGTGTTGGCTGCATCATCAAG ATCTCTTCTGAGAAAACTTGGTGTGAAATGAAGATTATAAAGAGA NEDD4 ATTTACTTTATCACATACCTATCTGTCTATCCATCAGTCTGTCTTA 3964 GTTTCTTCATGCATTTCAGA NFASC GTGGAAGTGGAATACTGGAAGAACCCAGCAGATCAACTCTGAGCTG 3965 CCCTTTGCCCTTTCAGAAAGTATCTCATTCCAAACAGTTCTTCGAA ACTAACCTCTTGCCCTCCAGCTACAGA NGF GTTGGTAGAGGTGCAGCAATTTTTGCAGTGAAACTGAAGTCCAGCT 3966 GCTCAAACAGAAATGGCCTCATCTAATGGACACTTTAATGA NIPA1 GTATTAAAGGAAGTAATCCGGTCCATACCTGAGCCTGGTATGCCCT 3967 CCTCCCGGACGTTCCTGTTTTCTGATCGTCTTCAGCACAGACATGA NLGN1 TGACTGCTCATGAAAGAAATTAAAATGATACATCATCAGTGGATCT 3968 TCCTGTAGA NLN CTCACTGCTTAGAATCTAAGGAGACAAGACCATAATAAAGGACAGT 3969 GTAGAAGACCTGAAGTTTTAAGCTCCAAATCTCTTAGCTACCAAAA TAAATAAATACTACAGAGCTGTTTGTGAGCAAGAGAAAACATCTAG ACAGA NREP TGTTCCAGGGCGCCATTAACGATTGGAGTTGGCACAAAATTTGAAA 3970 CTAGAAGTGGACTATTTGCTCCTTGAGA NSUN4 GGGCTCAGGAGTCCAGCGGTCCTAAGTATACCTTGCAGCCATCTTC 3971 CTAAAAGTTCTGACCATGACTGAGGACACTGAGAAGGA NUPL1 ATGAAAACTACTCCAATCAACTTCTTCAATCTGTTCTGCCACATTT 3972 TAGCCAGA OSBPL3 TGATGACAAATAAATGGTTCCAGCCTAAACTGACAGCCAGATACCA 3973 TTGTCCAGCTTTTTGTCTCATGGAAGCCGCACGCTTCAAATATGCA CCAGGTGCATTTCTGTTGCTGGATTGGGCTCTGAGCAATCTGATGT CCCCTGAAGAAGTGGATTGTGAAGGCCATGGATGGAGCAGGGAATA GAAATGGATACTCTATTGTGCCAGA PAPD4 AGCTCTACCTCTGTTTTGAAATGTCATTAGTTTGGATATGTTACCA 3974 GGATGCAGCAAAGAAGA PBX3 TGTTTTGAAATGCTTCAGAGAATGTGCGATATCCTTATCAACATGA 3975 TAAAATATGAAACTGTGATTGCCTGCAGCATTTTACAGACATGAAT TCCATCTTCACTGATGAGGCTTGATAAGGCGCTGTTGTATAATACA GTGCATAATCTCAAACCACCAGA PCDH10 TGAACAAGTTACCAGATCCTTCTCCTCTGAACTCGGGTTGCAAAAA 3976 AAGCCTTCAGTTCGGCTCTGGACAGCATTTACAGACGCTCTTGAAG CCGAGCGCCCACAGTGTGAATTTGAATGAAGCTGCGTTGGCACAAA CCCCTGTTAAGA PDE3A CTACATCATCTTTTCTAATTAAGAGAAAGAGAGAAAACCAGCGTGC 3977 AACTTAAAGACAGCTAAGGTTATCTTCTGAAAGATGCGGGTTCTTA CTAGA PDE7A CATGAAGGAATGGCCACAGGACAGGTGACTAGTCATTGTGGGATGG 3978 AATTATAGTCGATGAAGTGAGCCTTGGAGGAAGTCATGGTCCTACT CAGAGAAACAGA PDXDC1 TCTTCAAGGAAAACTATTTGATTTTCACATCTATGATGAGAGAAAA 3979 CAGAAAAATTGTCAAGA PDCDC2P TCTTCAAGGAAAACTATTTGATTTTCACATCTATGATGAGAGAAAA 3979 CAGAAAAATTGTCAAGA PELI1 ATTATCAAATACAGAAGTAGAAGCCAAGATTGAATGTGTTCCTGTG 3980 ATTGAAACTTTGATGTCACTGATAAAATATCCCCAGATAAGGCCTT CTAAGAGATCTAAGCAGA PIGN GGGCATACTGCAACTGTCAGTGCATACTTTACGGTGGGAAAACTTG 3981 GAGAAGGAATGGGTTAGGAAAAAATCAGTTTCTGAGGA PITPNB TGAGCTTGGAGTGAAGTCTAGTACGTCTGTGCAGCAAAGAGACCAG 3982 A PITPNB GCGAAAATGGGCAGTGTTTACAGGCATGAATGCTGGTGGAAAGAGC 3983 AGAGTAAGGGCAGATTGCACAAGAACCGTGGAGGCCCTGGTTCCCA TCACCTCCACCTCAGCACAGACTTCAGAGAGGAGAGGAGGCACTGG ATGCATGACAGCAGCACTTGAGATAGGTGCTCCAGGTGGAAGGCAC TGCACATGCAAAGGCTGA PMS1 GGATTCCCCCAGCAGACGTTTTTCATCTAAGAAATGGCTTGAGTGC 3984 TTCCTTTTATCGGGTGCTGTGATAGATTCTCAAAATATGAAAATGA PNISR ATTTTGCATTTGTTGGATTTGTTAGTAGTGAAGATACTATGGTGAA 3985 GATGAAGGAAGAAAGA POMT2 ATGTCCACTTAAAAAAATCTGGCGATGGGAGCAGAAAGA 3986 PPARG ATGGTGACTGATGCATCTCTAACACACCACATCACAGACTTCCTGA 3987 TCATCAGAAGA PPFIBP1 CCCTGTAATCTCTTCAAGAGATGATGATCTTTGATGGCATTTTGGG 3988 GGTGATGTTCAGGTGGCAGCCAGATTGGAGGGGACCGTGGAGCAGA CTGTGTGACTACTCATTCCAAGGGCATCATTGTGGAGA PRPF31 GACCGAACTCAGAGGCCACCTCATCCTATTAAACCTGTTCTGGTTC 3989 CTGACATCCCCCGACCCACACGA PSMA4 CAGAGAGACGCAACATCCACAAGCTTCTTGATGAAGTCTTTTTTTC 3990 TGAAAAAATTTATAAACTCAATGA PXK CTGTAAAGTTTGACTGAGAAATGTTGCATCAGCCCTGAAGTTTATT 3991 GAGAAAATCTTACGCTGATGCAAACTTTTTGGACTGTTAGTGTCTT ATGA RAB23 AGTGCTGGAATATGAATGAGCCAAATTGTGCTGTTCCATTGACACT 3992 GGTTGCTACAGAATTAACTTTACTCGGAGATCCGAGGAGCCATCGG CAGTTCCCAGGAGTAAGAACCTGAGAGCGTGTGAGA RAB23 AGTGCTGGAATATGAATGAGCCAAATTGTGCTGTTCCATTGACACT 3993 GGTTGCTACAGAATTAACTTTACTCGGAGATCCGAGGAGCCATCGG CAGTTCCCAGGA RAF1 AATAACAACCTGAGTGCTTCTCCCAGGGCGTGGTCCAGACGATTTT 3994 GTTTGAGGGGAAGA RAPGEF1 AGTGAAAACGCCAGTGAGGAAGCTGGTGAGGGTGAATATGTCAATC 3995 TGTATTCCTCTGGCCAGAGCAGCGAGGAGCTGGCTCCCTCTCGAGG A RASIP1 CCGAGCGTGGTGACGCATGCCTGTAATCCCAGCTACTCGGGAGGCC 3996 GAGACATGAGAATAATTTGAACCCAGGAGGCAGAGGCTGCAGTGAG CCAAGATCGCGCCACTGAACTCCAGCCTGGGGGACAGAGCGAGACT TCGTCTCGAAAAAACAAACAAACAAACAAACAAAAAACTGTCCTCC AGAAAAAGAAAAAGGAATTGGAGACCTAGGAGCCGGAAGA RBBP8 GACCATCTTAAGCAAGTCTCTTCTCCTGTGCTACTTGACGACTCTT 3997 TTGATACATGAAGACAGCTATCATGGCCCTCCTGAGTCTTGTTTTC TCTAGA RCOR3 GTTAACTACTGTGAGATAGTGGGGCCCCAATGAAACATATAAGCAT 3998 ACCTTTTAAAATGTTGCCAAATAGTCTTCAGAGAACATACTTAATA CAAAAATGCTGTGCAGACATCATTCCGATTGATCGACTGATGGATG ACTCCGCAGTTTGGATTAGAGAGA RERE CTGAAAAGGAGATGAAGATCCTGCTTGTAGCTGAGCAGTCTTTAGA 3999 AGTCTGCTGCATTCTTCCCAAATTCCATCACTCTAGTCAAGA RGL1 GGTGAGGAGCAATCTGTGGGAAGTCAGTGCACAGTAGAGTTCAGTC 4000 TTCCAACGCTGAAAATTTGCCAACTTTCACCCACACTGTGGAGATG AGAAAGCAGCTGTGGGCAGACAGTAGA RNF130 AATGGTTTATTATTGCCAGTTTTGGCCTCCTCAGTGCCCTCACACT 4001 CTGCTACATGATCATCAGAGCCACAGCTAGCTTGAATGCTAATGA RNF144A GAAGACTTTGCCAGTCTCTGGTCCACACTGTTACTGGACTTCAGGA 4002 TAGCACATTGTTCACCACAGAAGGAAAGATGTGGAAATTAAGA RNF213 AACGTGTCCCTAGTGCTAAGTGGCGCGGGACTCTGCTTTGCCTGCT 4003 GTCCTGCGGAGGCAGGAGGTGACCAGGAGAGTGA RPF2 GGTACAGGATACAGTTTGACTACTTAAAGTTTGAAGAAAAAAGAAG 4004 AGTAAGAAAGA RPS10 GTCCTCATAGCACACGATTGCTCTCAGATAATGTCATTTGTAAAAA 4005 GGAAGCATGTACAGTAGAAACGGTCCAATCCTGGTGCTGGATGCTT TCATAGGA SAMD4A AACTCCAGGTTGACCATGGCAGAAAGGGCTCAGATTCCCCTTCCAG 4006 TGCTTCTTGCCAAAATCTGGGAAATAGGAACCAGA SCO1 AGAAAGGATTTGAACTTGGCCTTCATGTATCAACTAAGTTAATCGA 4007 GCCTTGAATTGAGA SENP6 GCATTCTGTTCAGGCAGCAATTTGGAAATCCACCATTTATCATGA 4008 SF3B3 ATTTAACATTTTTGAGTCAATCCAAGTAATGCAGGAGGTTCATGAT 4009 TGTGTAGA SGIP1 TAGAAACAGGGTTTCGTCGTGTTGGCGAGGCTGGTCTTGAGCTCCT 4010 GACCTCAGGTGATCCACCCACCTTGGCCTCCCAAAGTGCTGAGATT ACAAGCATGAGACACTGTGCCAGGCCAAGAGCTTTGGAGTTTTCTA AGGAATCCAGTGAATACCAAGTTCCATGCTTATGAAAGA SGMS1 GCTCTTCTGGAACCCTGGACTCAAGTGATCCTCCTGCCTCAGCCTC 4011 CTGAGTAGCTGGAACTATAGGCACAAGCCACAGCACCGCCTTCAGT CTTTGCTTTGAGTAGA SGPL1 GCCTTTGAGCCCTACTTAGAGATTTTGGAAGTATACTCCACAAAAG 4012 CCAAGAATTATGTAAATGGACATTGCACCAAGTATGAGCCCTGGCA GCTAATTGCATGGAGTGTCGTGTGGACCCTGCTGATAGTCTGGGGA TATGAGTTTGTCTTCCAGCCAGAGA SH2B3 GTGGATTCCTAGAAGTGGCATTGCTCAGTCATAGA 4013 SKP1 GGACAACTGCATTATTGGCAAGCGCTAAGCAACATGGAGAAGCAGA 4014 CATGTTTGTGAATCGCAAAGTGAAATCTGATTCTCTCCAACTATGG ATGAGTGAGA SLC12A2 TCAGCATTTTGTAGTTTTCAGCATATACGTCCTGTATGTATTTTGT 4015 TAGATTTACGA SLC25A16 CCAGGCTTGGTGGTCCCAGCTACTTGAGAAGCTGAGTTAAGAGGAT 4016 TGCCTGAGCCTAGGAGGTTGAGGCTTCAGCGAGCTGTGATCATGCC ACTCTACTCCAGCCTGAATGACAGA SLC25A17 ATTTGTTCAAGTTGAAATTGTAAACCTATGCCAGAACTTGCATGAA 4017 GAGATGA SMOX CTGGGAAGACTGAGGCACAGTCATACAGCTAAATAGTGACAGAATG 4018 AGGATTGAATCCAAACATTTTACAGACGGGAGGACTGAGTCATAGT CATACAACTAAATAATAACAGA SNAP23 TATTGGAATATGACAGGGAAGATGAATTCACTATGA 4019 SNX24 AAGAATGTTCCTTTTGTGAAGAATGACTTAAGGAAGATTCATGATG 4020 ACTGAGTGTGCCCGTGTGGAACTTTAGGACATAGATGCACTCCTAC AGA SNX7 AGTTTGCAAAGGAAGGAAAGGAGCAGAGACTTGAATGAGCAGAAAA 4021 TCATTTCAGGGCCTGTTCTCTATGTCCTTGCTATCCCTGTCTTCTG TAGCTATTCTGAAACCATCAACAAAGGAGCACACCATTCCATCAGC AAAAGA SOCS6 AATCCACAAAAATTAGCCGGGTGTGGTGGCACACACCTGTAATGCC 4022 AGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGGAGT CAGAGGTTGCAGTGAGCTGAGATGGCACCACCACACTCCAGCCTGG GCGACAGA SOGA2 TTCAGCAGTGCAGAGAGAAGCCGTGAGGAGTTCCGGTGTGAAGAGA 4023 AAGAATCTGAAAATGGAATGCTCTTCCTCCCTCCCCTAAGTGGAAA ATGTGAGGGGAACTTTTTAGA SORCS1 ATATCGCAGCACATTGCAAAGTCTCTGACACCTTTCCCTTTCCAGT 4024 GTCATTAAATGA SPIDR GTATTCAGTAGAAGCAGATGAACAGCCAGATGAAGAGATGGATAGA 4025 GCAAGACATGGACATTATAAAGGAATTCAATAGAAGCACATGAACG GCCAGATGAAGAGATGGATAGA SPRYD7 GTGTGGTTGTACGTGCCTGTAGTCCCAGCTACTTGAGAGGCTGAGC 4026 TGAGAGGATCTCTTGAGCCGGGGAGGTCAAGTCTCCTGTGAGCAGT GATCATCGTGCCGCTGCACTCCAGCCTTGGCACCAGA SREK1 GGTGGCTGCACTCAACGAGTTTATGCAATGACTTTCTTGGATGTTT 4027 CTGAAGGAGGAGGATGTACAGAGA SSBP1 GAGGCGGATCTTGGTCAGTAATGCTTGCTCGCTGCTTGCTGCTCAC 4028 CTCCTGCTGTGCAGCCAGGTTCCTAACAGGCCACAGAACTCTACTA GTCCTCAGCCCTGGAGGTTGGGGACTCTCCTCTAACTGGCTGTTCG TTATGCCTGAGA STRADB AACTAGGCTTGGAAGAAGCCAAGAGAAGCTGCATGACAAGGACCAG 4029 GACTGTGGAATAGGAGCAGCCTAGTGAATGTACTGCCCGCCACCAG ACGCTGGCCCCCTGCTGATAGCTCTGACGACTGCTGCTGCTTTGTC CTTCACTCCGTACTCCAGTTGGCCAAGCATAGGTCGCATGCCAGGG TCAAGGAGACTAAGGGAGA STXBP4 GTTTAACCATGGTTGGAAATGACAGA 4030 STXBP6 AATGTAAGCTCCATGAGGGAAAGTACTTTGTTGCTCTTCTTCTCCT 4031 CAGTATCCTCAGCGTTAGGACAATGCAGTGATATTGAATGA STXBP6 GTGGTCCCTGAGTTAAGAACATGCAATGGCACTCTCTCAAGGAGAG 4032 GAAGGAGCCAAAGAAGAAAGAGGTCCAAAGCAGAAAAGAGCAGACA GCTAAGA SUPT20H TTGAAGACGATAATTCTAACTTCCTGTCAGTTGAAGACGATAATTC 4033 TAACTTCCTGTCAGTTGAAGACGATAATTCTAACTTCACACTTAAT TAAAAGA TAF2 GAAGATGATCACCTTGCCAAGGAAGCATCATGTAATATATCAGCTC 4034 ATCAGCAGGGAGTGAAGAGGAAGTCTGATACACCACTGGGGTCCCC ACTAGAACCTGGTCAAATACTGGAGAAGAATGAGGATAGCAGTAAA GTCAAACTCAAAATCAGA TAF2 TTTTGAGATCCACCAAATATGTCATTGTTGCCAGTCTTCTTTCCCA 4035 AGATGTATGGATAGTTTTTAATGTCTCATAAATATGA TARBP1 CCGATTTCAGCCTACCAATGTGAGGCCACTGAGTTGGAAAGAGATA 4036 TGATCTTCGGTCTTTGCGATGCTGGCTGGGTCTGCTGCTACGCCGC TGCCTGTCTTAGTTCACAGAGGAAATAGTGGCTGTCAGGCTGGAAT GCTCTCAATTTCCAGTTGCCAGATGTATGGACTTACGCTATATGCT CAACCACACCTGAATTCATCCTCCCTGTCTTCCCTTTGTTACAAGA GA TASP1 CTTTGGACCTTCCTCTCCCTCTGGTTTCCTGACTTCTATAAAAGAA 4037 TAGTTGAACTAACTAGTGGCATACCTGTTCAGCATCATGACTGGTT TCCGAAACATGTTCCTCCATAATGTTGAGAGCCGTGGTAGCGAAAT GA TBCA ATCCCGCTATCTGTCCTGTGATGCCATACTAGA 4038 TBL1XR1 ATTCCAGAATGAAGAAGATGCCTGTAGCCAACCTGTAGCTGACAAC 4039 AAAAATGAGAAATACATTTTGCGCTGTCTGTTGAACCCAAGACCCT TTCAGA TCF4 GATTTGCCTCCAAGAAAAAATATATTTTATTGCCACATTTTCTCAA 4040 TTGATCCAGTAGAGTTCACAGACAATGAAAAGA TEKT4P2 TTGAAGAGATACCATTTGACATTTTAGAGATGGCTGCATGCAAACT 4041 CTTAAAACATTTGA TET1 AGATCATGCGTAATATTCCTGTTTCATGGGCCATAAGGACATGTGT 4042 TTAATTCATAAGGACATATGGATTCCATTTGAAACAGGATCTCACA CAGA TIAM1 ATACCAGAGAAGCGTGAACATATTGCTTTGAAATCTACTTGCTCCT 4043 AGTAAAAAAGAGATTGTCTTTATTGGAAAATTCCCTCTGAGATTCC TGTGATGTGTGACCTGGTGGGGAATATTCCAGCCTGGGAACAGCTT AACATCTGGTGTCTGTATGAGTTACCCCTGAACTCACTGGAACATT CAATGGAGGGTTTCCCTTTGTGTTGCCACAAATTTTATTTCAGTGA AGATGTGCTGGTGAGAGTTTCAGCAACGTTTTAGCCTGAACAGTGG AATTATAGA TJAP1 GAGTAAGATCTTCTGTCTCTGAAGCTTCTTAGGGGCAAGCTTTTTT 4044 ACTGAAGGCCAAGCATTTAGGCACTATAGA TJP2 GGATTGGTGTCTCTATCATCCAGCTGGCCATTAAACAACCAAAGCT 4045 TCATCATCCTAGATAACCTGTGAGCTCTCAGAGGAGACAGA TMEM214 CCATCCTAGATCTGAGATTTGCAACCTGGAAGTTCAAGA 4046 TMX3 GGAAGGTAATGAGAATTATAGTACTTTAATTTTCCAAGCTCTTGAC 4047 CATGAATGTGTAGATTATTTTTCAGAAGGCGTAGATACAATGCAGT TATCAAATGCAGA TNRC6A GATGGGAGAGAGAAGAGCATGAAAGAAGCGGTTGGGATTAGCCTTC 4048 TTCAGTAACATACCCTGGGGTCGTCCTTTGGAATTTCATGGTTATT GTGGTGTATGTGACCACATTTAGAGTGCACTGCCTCAGACCTGCCT TAAAGCTGTGTCATAGGATAAGA TRAF3 CACCAATACATTATTATGAAGTCAGTACAGAGAGATTGGCATCTTA 4049 GTATTTTCTGAGGAAGAGAACAGCCAAAGA TRIM65 GCCCCAGGTCCCCTGGCACCGGTCCCAAGCACAGTTTGTCCACTGA 4050 GGAGGAAACTCTGGCAGA TSPAN7 GTCTATAGAAGAGGAGGGAAAAACACACCTAGGA 4051 TXNL4B TTGTGGCGCGCGCCTGAGGTTCCAGCTACTCGGGAGGCTGAGGCGG 4052 GAGGATTGCTTGAGCCTGGGGAGTTGAGACCAGCCTGGGCAACATA GCGAAACCCCGCCTCAGAAAAAGAGAGGGAGAGAGGAAAGCAGTGG AGTTATTGGTCAAAGA UBE2D3 GTGCTGTATAAACAGATGAGAGTGCCCCCACAGCATTGTTATTAGA 4053 UBE2L3 AATGACCACCTGAGAAGGAGTGTGCTGTAACCTCTGAGAAGCACTG 4054 TGCTGTGATAGA UBN2 GATCACAACTTTTACAGATTTTTAAAATATTGGCCGGGCGCAGTGG 4055 CCCACACCTGTAATCCCAGCACTTTGGGAGGCTGAGGCAGGAGATC AAGACCATCCTGGCTAACACGATGAAATCCCGTCTCTACTGAAAAT ACACAAAATTAGCCAGGCGTGGTGACACACACCTGTAGTCCCAGCT ACTTGGGAGGCTGAGGCAGGAGGATCACCTAAACCCGGGAGGTGGA GATTGCAGTAAGCCGAGATCGCGCCACTGCACTCCAGCCTGGGCGA CAGA UNC13B GTCACTGGACCTATTTGGGCTGGGGAGAACAACAGA 4056 URGCP-MRPS24 GCTTTGGGGCAGTGGTCATTTCCGGGACCAGGCCTTTTCATTGCCA 4057 GCTGACTACCCAGCACTTTGAGCTCATGAATAGA UVRAG GAACAAAGCCTGAGCCTCCAAGCCAGAAGCAAAGTTTGTATGCGTG 4058 GTTAGACAGGTTGTTTCTGATTGGAGAGAACCTGGAAAGAATTAAG CCAGTCACACACAGGTCCATCTCTGAAGCCCAGCCATCAGATCAGT CATCTGCTGGTCCTGGAGAGGAGTGAGTGGAGGACACAGAGAAACT GCAGATGCTCCTTTCATGACCTTTTCTCCTGAGAAATGGAGTGGGG CATTTGTCTCCTGTGTGGGAACATGGGAATGCAGA VDAC2 ACATGGCAGCCCCTAGCATGTGTATCCTAAGA 4059 WDR27 AGCTGCCCCTGGAGCAGAATATTCCCTGCTTGGTCCAAACCACAGA 4060 GA WDR90 CCTCCTGGCAAGGAGCAGAGCTGGCGGGAGGCGGCTTTGGGGAAGA 4061 ATCTCTGTCCACAAAGA WHSC2 GCTTTCTGCGGGAGCAGTGGTGGCCCCGGCTTCTCACCCTTCAGGT 4062 TTTCTTGCATCTGCGCACCGGTGGAAGA WNK1 GTTGTCCAACATGTGAGCATTTTCTGGCTGGGGAGA 4063 XRN2 CCATCAACAACTCTTAGCTGAAAGAGGGATAAGGCCCAAGCAAGGA 4064 TAGAGAGA ZFP82 ATCTTTGTACATTATCCCTGTGTTGAAATGCAAATAGGACTTCCCT 4065 GGAACCAAATCTTCTATATCCCAGAACTTCTTGTATCAACAAAGTA AGATGGTTGATACAGTGCCCAAATAGA ZMIZ2 GGGCACAGGGTCAAGGATACCAGACCTGGAGACTGGAAGTCTTTTC 4066 AGAGAGACTGTCCTCAGAGAGGAGACCAGAGGCATGAGTTCGGGTC GGCAGGAAATCCCCCTGTGCAGTGAAGA ZNF138 GCCTCTGGAAGAGCAGGACCTCTCCCAGACTGTGATTGGGAGGAGT 4067 TTGGGATGGTTACAGA ZNF208 GCTTCTGGAAGACAAAGACCTCTCACAGACTGTGGCTGGGAGGAGT 4068 TTGGGATGGTTACAGA ZNF212 GAGGATGTATTTAAGCTTTTGTCTCATGTGTTCCATGATGAATTAA 4069 CTGACTTGAGTAACTAGA ZNF280D AAATCAAGAAGTTTTAATATTTGAGCAGTGCTTATGGAGGTTTTAA 4070 AGAGAATATATTCCTCAAAATTCTAATTACTTCTGTGATTTTACTG CCTCCAGA ZNF350 AGTCTTGCTCTGTGCCCAGGCTGGAGCGCAATGGTGTGAACTTGGC 4071 TCACCGCAACCTCCACCTCCTGGATTCAAGCGATTCTTGTGCCTAT CCCCAACACCAGCACCATACCTGGCACACGGTGATCATTCAGTAAG A ZNF37BP AGTCAAGAACAGACACTGAGTCGCTTGAGGACTCAGGCAGGTGTTT 4072 GCTGCATTGACAACAGA ZNF426 CTACTCAGGAGGCTGAAGCAGGAGAGTTGCTTGAACCTGGGAGGTG 4073 GAGGTTGCAGTGAGCCAAGATTGCACCAGTGCACTCCAGCCTGGGC AACAGA ZNF618 AAACTGCAAGTCCCCTGATTTCCAACCCTTTCCCTCTCCTACAGA 4074 ZNF680 GCAGAACTGGCCGTGAACTGTGGCTCAGGGAGCTGGAACTGAGTCA 4075 TCGAACTGCTTCAGAAACCACAGTAAAGGACAAGGTCTGCAGGCCT GCCTGCGTGGCTATAAATGGCTGTCTTCCTCCAGGCCTCTGGAAGG GCACGGTCTCTCCCAGACTGTGGCTGGGAGGAGTTTGGGATGATTA GAGA ZNF730 GCCTCTGAAAAGGCAGGACCTCTTCCAGACTTTGGCTGGGAAGAGT 4076 TTTGGATGGTTTCAGA ZNF777 GCCTCACTACTTCCTCATTCCCCATGTCGGAAACCCCAGGGTGGAA 4077 CCCAGACCACCTGAGCACACCTGCTGCAATGGACTGCTGCCCACTC CTAGGAGTGGTTGAATTGCCTGCCTTCACCTGCCTCGATGTCTCGC TCTGCTTATAGCAGAAGCCAGGCCAGAATACCCAGAAGCCCGTTCA GCCTCTACAGCAGGGGCCGGGCACATAGAAGATGTTTCCAAGTCAA ACATACATATACCATACTGACTCATTGATATGAGTCTGCAATGCAA CTGTTATCAAAGA ZNF804A CTCTCTGTGTCAGATTTGACCTTGGAAGATCACAGAGGAAAAGCGA 4078 GAAGGA ZNF836 TGCCTAAATGAAGACGTATGGGTCTTTTACTGTTTTTTGCTGTTAC 4079 AAAGAATGTCACCGTGGCTGCCTGTATGCATGCTATCTTTACCACA GATGTCTGAAGTTTCCTCCAGGTTGGGCAGTTTAAAGA ZSCAN25 GCTCTGGGTGATCTGGTTTCTGTCTGCCTCTGCCACCTCTTCTGGT 4080 GCAGCTCTGCTCGTCACTGCTGAAGCCACACTGGGATATGGCTTGT TCTTGGACACCCAGA
(454) Results:
(455) For certain genes, where the values for splicing modification may have been considered statistically insignificant, the values in those instances prompted manual examination of RNAseq data for the likelihood of iExon production inclusion. Those events that demonstrated qualitative reads to support iExon inclusion were subsequently validated by end-point PCR. As demonstrated herein, the presence of an iExon has been demonstrated and validated for numerous targets.
(456) It will be appreciated that, although specific aspects of the invention have been described herein for purposes of illustration, the invention described herein is not to be limited in scope by the specific aspects herein disclosed. These aspects are intended as illustrations of several aspects of the invention. Any equivalent aspects are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description, which modification also intended to be within the scope of this invention.
(457) All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.