TEAD inhibitors and uses thereof

By developing small-molecular compounds that selectively bind and inhibit TEAD, the cancer problem caused by the interaction between TEAD and YAP/TAZ is solved, and the targeted treatment of the Hippo pathway is achieved, which significantly inhibits tumor growth and is harmless to normal cells.

CN114466839BActive Publication Date: 2025-01-07IKENA ONCOLOGY INC
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Patent Information

Application Number
CN202080050337.7
Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
Priority Date
2020-05-15
Filing Date
2020-05-29
Publication Date
2025-01-07
Estimated Expiration
2040-05-29

AI Technical Summary

Technical Problem

The prior art is difficult to effectively inhibit the interaction between TEAD and YAP/TAZ, leading to the promotion of cancer and tumor growth, and traditional methods have potential toxicity and side effects on normal cells.

Method used

A new small molecule compound that selectively binds and inhibits TEAD to prevent palmitoylation of TEAD and YAP/TAZ, thereby downregulating YAP/TAZ-dependent transcription, which is used to target the Hippo pathway and specifically inhibit the proliferation of cancer cells. It does not affect normal cells.

Benefits of technology

In vivo and external experiments, this compound can effectively inhibit YAP-dependent gene expression, significantly inhibit tumor growth, and is harmless to normal cells. It has a single-agent tumor growth inhibitory effect, proving that it is a safe and efficient cancer treatment method .

✦ Generated by Eureka AI based on patent content.

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Abstract

The present invention provides compounds, compositions thereof, and methods of use thereof.
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Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: L 1 is -NH-CH2-; Ring A is phenyl; optionally substituted by halogen, -CN, -NO2 or -C 1-6 The aliphatic group is substituted 1 to 2 times, the -C 1-6 The aliphatic group is substituted 0 to 6 times by halogen, -CN or -NO2; R 2 yes R 3 Yes - H; R 4 is -S(O)2N(R)2 or -S(O)N(R)2; R 6 Is -H or -C 1-6 The aliphatic group, the -C 1-6 The aliphatic group is substituted 0 to 6 times by halogen, -CN or -NO2; and Each R is independently -H or -C optionally substituted with halogen, -CN or -NO2 1-6 aliphatic groups; Wherein the compound of formula I is not:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted with -C 1-6 The aliphatic group is substituted 1 to 2 times with a phenyl group, wherein the -C 1-6 Aliphatic groups are substituted 0 to 6 times by halogen.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 yes and R is unsubstituted -C 1-6 Aliphatic group.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is -S(O)2NHR.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 Yes -H.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IXa-1) or (IXa-2): wherein each R is independently -H, unsubstituted -C 1-6 aliphatic group, or -C substituted 1, 2, 3, 4, 5 or 6 times by halogen, -CN or -NO2 1-6 Aliphatic group.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Xa-1) or (Xa-2): wherein each R is independently -H, unsubstituted -C 1-6 aliphatic group, or -C substituted 1, 2, 3, 4, 5 or 6 times by halogen, -CN or -NO2 1-6 Aliphatic group.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (XIa-1) or (XIa-2): wherein each R is independently -H, unsubstituted -C 1-6 aliphatic group, or -C substituted 1, 2, 3, 4, 5 or 6 times by halogen, -CN or -NO2 1-6 Aliphatic group.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (XIIa-1) or (XIIa-2): Where R is -C substituted 1, 2, 3, 4, 5 or 6 times with -F 1-3 Aliphatic group.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (XIIIa-1) or (XIIIa-2):

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (XVIa-1) or (XVIa-2):

12. The compound according to claim 1, which is selected from: or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II): Where L 1 is -NH-CH2-, R 1 is -H, -halogen, -CN, -NO2, or -C substituted 0-6 times by halogen, -CN or -NO2 1-6 an aliphatic group, and R 7 is -H, -halogen, -CN, -NO2, or -C substituted 0-6 times by halogen, -CN or -NO2 1-6 Aliphatic group.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 yes 15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 It is -S(O)2NH-CH3.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.

17. A compound: or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising the compound according to claim 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.

19. A compound: or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound according to claim 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.

21. A compound: or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising the compound according to claim 21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.

23. A compound: or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising the compound according to claim 23 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.

25. Use of a compound according to any one of claims 1 to 15, 17, 19, 21 or 23, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating cancer in a patient, wherein the cancer is associated with increased TEAD expression or increased TEAD activity.

26. The use according to claim 25, wherein the cancer is associated with increased expression of TEAD.

27. The use according to claim 25, wherein the cancer is associated with increased TEAD activity.

28. Use of a compound according to any one of claims 1 to 15, 17, 19, 21 or 23, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or disorder associated with increased TEAD expression.

29. Use of a compound according to any one of claims 1 to 15, 17, 19, 21 or 23, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or condition associated with increased TEAD activity.

30. The use according to claim 28 or 29, wherein the disease or disorder is a cell proliferative disorder.

31. The use according to claim 30, wherein the cell proliferative disorder is cancer.

32. The use according to claim 25 or 31, wherein the cancer is a cancer in which YAP is localized in the nucleus of the cancer.

33. The use according to any one of claims 26, 27, 28 or 29, wherein the increased TEAD expression or increased TEAD activity is increased TEAD1 expression or increased TEAD1 activity.

34. The use according to any one of claims 26, 27, 28 or 29, wherein the increased TEAD expression or increased TEAD activity is increased TEAD2 expression or increased TEAD2 activity.

35. The use according to any one of claims 26, 27, 28 or 29, wherein the increased TEAD expression or increased TEAD activity is increased TEAD3 expression or increased TEAD3 activity.

36. The use according to any one of claims 26, 27, 28 or 29, wherein the increased TEAD expression or increased TEAD activity is increased TEAD4 expression or increased TEAD4 activity.

37. The use according to any one of claims 26, 27, 28 or 29, wherein the increased TEAD expression or increased TEAD activity is increased TEAD1 expression or increased TEAD1 activity; increased TEAD2 expression or increased TEAD2 activity; increased TEAD3 expression or increased TEAD3 activity; increased TEAD4 expression or increased TEAD4 activity; or any combination thereof.

Citation Information

Patent Citations

  • annular gap magnet system

    FR901228A

  • Deacetylase inhibitors

    US6552065B2

  • Apoptosis promoters

    US7390799B2

  • Quinoline derivatives as PI3 kinase inhibitors

    US8138347B2

  • Methods for treatment of cancer

    US8906682B2