INHIBITORS OF SHP2

Abstract

The present invention is related to an inhibitor or antagonist of SHP2 for the treatment and/or prevention of a neoplastic disease.

Claims

1: A method for treatment or prevention of a kidney disease, comprising administering to a subject in need thereof an effective amount of an inhibitor or antagonist of SHP2.

2: The method of claim 1, wherein the inhibitor or antagonist is an allosteric inhibitor or antagonist.

3: The method of claim 1, wherein the inhibitor or antagonist is a monoclonal antibody, or a target-binding fragment or derivative thereof retaining target binding capacities, or an antibody mimetic, which specifically binds to the SHP2 protein.

4: The method of claim 1, wherein the inhibitor or antagonist comprises a first nucleic acid molecule that specifically binds to a second nucleic acid molecule, which second nucleic acid molecule encodes for the SHP2 protein.

5: The method of claim 1, wherein the inhibitor or antagonist is an aptamer that specifically binds to the SHP2 protein.

6: The method of claim 1, wherein the inhibitor or antagonist is a small molecule that specifically binds to one or more isoforms of the SHP2 protein.

7: The method of claim 1, wherein the inhibitor or antagonist can be found by means of a SHP2 inhibition assay.

8: The method of claim 3, wherein the SHP2 protein to which the antibody, fragment or derivative, or antibody mimetic binds comprises SEQ ID No 1.

9: The method of claim 6, wherein the nucleic acid encoding the SHP2 protein comprises SEQ ID No 2.

10: The method of claim 1, wherein the inhibitor or antagonist is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

11: The method of claim 1, wherein the inhibitor or antagonist is ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl}methanol.

12. (canceled)

13: A method for treating or preventing kidney disease, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an inhibitor or antagonist of SHP2.

14. (canceled)

15: A method for treating or preventing a kidney disease, comprising administering to a subject in need thereof an effective amount of a combination comprising an inhibitor or antagonist of SHP2 and one or more therapeutically active compounds.

16: A method for identifying a compound for use in the treatment or prevention of a patient suffering from, at risk of developing, and/or being diagnosed for a kidney disease, which method comprises the screening of one or more test compounds in a SHP2 inhibition assay.

17: The method of claim 16, further comprising a prior step of creation and/or provision of a library of test compounds.

18: A method for determining whether a human or animal subject is suitable of being treated with an antagonist or inhibitor of SHP2, said method comprising providing a tissue or liquid sample from said subject, and determining whether or not said sample is characterized by expression or overexpression of SHP2.

19: The method according to claim 18, wherein the expression of SHP2 is determined on an mRNA level; on a protein level; or on a genomic level.

20: The method of claim 18, further comprising using a companion diagnostic, which companion diagnostic comprises at least one agent selected from the group consisting of a nucleic acid probe or primer capable of hybridizing to a nucleic acid (DNA or RNA) that encodes an SHP2 protein; an antibody that is capable of binding to a SHP2 protein; and an aptamer that is capable of binding to a SHP2 protein.

21: The method of claim 5, wherein the SHP2 protein to which the aptamer binds comprises SEQ ID NO: 1.

22: The method of claim 6, wherein the SHP2 protein to which the small molecule binds comprises SEQ ID NO: 1.

Description

FIGURES

[0114] FIG. 1 shows the results of the experiments of example 1. FIG. 1A: Timeline of the experiments

[0115] FIG. 1B: structure of RMC-4550. FIG. 1C: Results of the experiments

[0116] FIG. 1D shows the results of pERK HTRF assay

[0117] FIG. 2 shows the results of pERK HTRF assay of RMC-4550 and TNO 155 in immortalized human renal proximal tubular epithelial cells (RPTEC)

SEQUENCE LISTING

[0118] A sequence listing is enclosed which discloses the following sequences:

TABLE-US-00004 No Type Sequence 1 SHP2 MTSRRWFHPNITGVEAENLLLTRGV AA DGSFLARPSKSNPGDFTLSVRRNGA sequence VTHIKIQNTGDYYDLYGGEKFATLA Isoform 1 ELVQYYMEHHGQLKEKNGDVIELKY SHP2 PLNCADPTSERWFHGHLSGKEAEKL LTEKGKHGSFLVRESQSHPGDFVLS VRTGDDKGESNDGKSKVTHVMIRCQ ELKYDVGGGERFDSLTDLVEHYKKN PMVETLGTVLQLKQPLNTTRINAAE IESRVRELSKLAETTDKVKQGFWEE FETLQQQECKLLYSRKEGQRQENKN KNRYKNILPFDHTRVVLHDGDPNEP VSDYINANIIMPEFETKCNNSKPKK SYIATQGCLQNTVNDFWRMVFQENS RVIVMTTKEVERGKSKCVKYWPDEY ALKEYGVMRVRNVKESAAHDYTLRE LKLSKVGQALLQGNTERTVWQYHFR TWPDHGVPSDPGGVLDFLEEVHHKQ ESIMDAGPVVVHCSAGIGRTGTFIV IDILIDIIREKGVDCDIDVPKTIQM VRSQRSGMVQTEAQYRFIYMAVQHY IETLQRRIEEEQKSKRKGHEYTNIK YSLADQTSGDQSPLPPCTPTPPCAE MREDSARVYENVGLMQQQKSFR 2 SHP2 MTSRRWFHPNITGVEAENLLLTRGV AA DGSFLARPSKSNPGDFTLSVRRNGA sequence VTHIKIQNTGDYYDLYGGEKFATLA Isoform 2 ELVQYYMEHHGQLKEKNGDVIELKY PLNCADPTSERWFHGHLSGKEAEKL LTEKGKHGSFLVRESQSHPGDFVLS VRTGDDKGESNDGKSKVTHVMIRCQ ELKYDVGGGERFDSLTDLVEHYKKN PMVETLGTVLQLKQPLNTTRINAAE IESRVRELSKLAETTDKVKQGFWEE FETLQQQECKLLYSRKEGQRQENKN KNRYKNILPFDHTRVVLHDGDPNEP VSDYINANIIMPEFETKCNNSKPKK SYIATQGCLQNTVNDFWRMVFQENS RVIVMTTKEVERGKSKCVKYWPDEY ALKEYGVMRVRNVKESAAHDYTLRE LKLSKVGQGNTERTVWQYHFRTWPD HGVPSDPGGVLDFLEEVHHKQESIM DAGPVVVHCSAGIGRTGTFIVIDIL IDIIREKGVDCDIDVPKTIQMVRSQ RSGMVQTEAQYRFIYMAVQHYIETL QRRIEEEQKSKRKGHEYTNIKYSLA DQTSGDQSPLPPCTPTPPCAEMRED SARVYENVGLMQQQKSFR 3 SHP2 MTSRRWFHPNITGVEAENLLLTRGV AA DGSFLARPSKSNPGDFTLSVRRNGA sequence VTHIKIQNTGDYYDLYGGEKFATLA Isoform 3 ELVQYYMEHHGQLKEKNGDVIELKY PLNCADPTSERWFHGHLSGKEAEKL LTEKGKHGSFLVRESQSHPGDFVLS VRTGDDKGESNDGKSKVTHVMIRCQ ELKYDVGGGERFDSLTDLVEHYKKN PMVETLGTVLQLKQPLNTTRINAAE IESRVRELSKLAETTDKVKQGFWEE FETLQQQECKLLYSRKEGQRQENKN KNRYKNILPFDHTRVVLHDGDPNEP VSDYINANIIMPEFETKCNNSKPKK SYIATQGCLQNTVNDFWRMVFQENS RVIVMTTKEVERGKSKCVKYWPDEY ALKEYGVMRVRNVKESAAHDYTLRE LKLSKVGQGNTERTVWQYHFRTWPD HGVPSDPGGVLDFLEEVHHKQESIM DAGPVVVHCR

REFERENCES

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