The present disclosure relates to compositions and methods for the treatment of diseases or disorders (e.g., cancer) with bi-steric inhibitors of mTOR in combination with RAS inhibitors. Specifically, in some embodiments this disclosure includes compositions and methods for inducing apoptosis of tumor cells and/or for delaying, preventing, or treating acquired resistance to RAS inhibitors using bi-steric mTOR inhibitors.

The present disclosure provides compounds represented by Formula I: A-L-B.sup.1 and the salts or solvates thereof, wherein A, L, and B1 are as defined in the specification. Compounds having Formula I are androgen receptor degraders useful for the treatment of cancer and other diseases.

Improved processes for the preparation of tubulysin compounds, tubulysin drug linker compounds, and their intermediates are disclosed.

The present invention relates to an antibody drug conjugate (ADC) of general formula (I) (D-Lk.sub.1-C(O)-Lk.sub.2-C.sub.2H.sub.4—NH-Lk.sub.3).sub.n-Ab. A pharmaceutical composition comprising, in a pharmaceutically acceptable medium, the said ADC is also concerned by the present invention, as well as the use of this ADC or composition as a medicament, and in particular in the prevention and/or the treatment of an anti-Müllerian hormone type II receptor (AMHRII) expressing cancer in an individual.

The present invention relates to oligonucleotide conjugates and preparation and applications thereof. In particular, the present invention relates to an oligonucleotide conjugated to a biomolecule (e.g. an antibody) and/or an agent of interest (e.g. a drug). In certain embodiments, the oligonucleotide of the present invention is a hybridized complex of a single strand oligonucleotide carrying a biomolecule and a complementary strand oligonucleotide bearing an agent of interest where the hybridized nucleotide segment acts as a linker to link the biomolecule and the agent of interest in one molecule.

It is provided a cocrystal of a compound of formula (I) or of a compound formula (II) wherein X and Y are independently selected from —CH.sub.2— and —C(CH.sub.2)—, provided that al least one of X or Y is —CH.sub.2—; R.sup.1 is —CHCH.sub.3—Z.sub.m—W.sub.n—(CH.sub.2).sub.o-T.sub.p-S, wherein Z is O, and m is 0 or 1; W is R.sup.4CH CHR.sup.5, wherein either R.sup.4 and R.sup.5 are H and the dashed line indicates that there is a single bond, or R.sup.4 and R.sup.5 together are forming a bond and the dashed line indicates that there is a double bond, and n is 0 or 1; o is 0, 1 or 3; T is selected from the group consisting of —CHR.sup.6—, —C(O), wherein R.sup.6 is —OH or —CH.sub.3, and p is 0 or 1; S is selected from the group consisting of H, (C.sub.1-C.sub.3) alkyl optionally substituted by —OH, (C.sub.1-C.sub.3) haloalkyl optionally substituted by —OH, cyclopropyl, or; and R.sup.2 is —H or —OH; R.sup.3 is H or CH.sub.3; and the dashed line in formula (II) indicates a single or a double bond; and a hydrogen bond donor coformer which is a phenolic compound. It is also provided a composition comprising the cocrystal and a personal care product comprising the composition.

##STR00001##

It is provided a cocrystal of a compound of formula (I) or of a compound formula (II) wherein X and Y are independently selected from —CH.sub.2— and —C(CH.sub.2)—, provided that al least one of X or Y is —CH.sub.2—; R.sup.1 is —CHCH.sub.3—Z.sub.m—W.sub.n—(CH.sub.2).sub.o-T.sub.p-S, wherein Z is O, and m is 0 or 1; W is R.sup.4CH CHR.sup.5, wherein either R.sup.4 and R.sup.5 are H and the dashed line indicates that there is a single bond, or R.sup.4 and R.sup.5 together are forming a bond and the dashed line indicates that there is a double bond, and n is 0 or 1; o is 0, 1 or 3; T is selected from the group consisting of —CHR.sup.6—, —C(O), wherein R.sup.6 is —OH or —CH.sub.3, and p is 0 or 1; S is selected from the group consisting of H, (C.sub.1-C.sub.3) alkyl optionally substituted by —OH, (C.sub.1-C.sub.3) haloalkyl optionally substituted by —OH, cyclopropyl, or; and R.sup.2 is —H or —OH; R.sup.3 is H or CH.sub.3; and the dashed line in formula (II) indicates a single or a double bond; and a hydrogen bond donor coformer which is a phenolic compound. It is also provided a composition comprising the cocrystal and a personal care product comprising the composition.

##STR00001##

Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in a mRNA expressed from a mutant DMD allele.

Provided are a double-stranded siRNA analogue embedded with a ribavirin derivative, a conjugate containing same, and a salt and the use thereof. The provided double-stranded siRNA analogue, the conjugate containing same and the salt thereof can effectively inhibit multiple viral indicators such as hepatitis B virus DNA, pgRNA, S antigen, and E antigen, which provide an effective and feasible method for treating hepatitis B.

Disclosed is a dTAG system comprising small molecule degraders of mutant BET family protein-tagged proteins via recruitment of an E3 ubiquitin ligase and uses thereof.