Mediators of hedgehog signaling pathways, compositions and uses related thereto

• US 20050080138A1
• Filed: 09/29/2004
• Published: 04/14/2005
• Est. Priority Date: 09/16/1999
• Status: Abandoned Application

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Rubin, Lee, Guicherit, Oivin M.
• Application Number:
  US10/953,601
• Publication Number:
  US 20050080138A1
• Time in Patent Office: Days
• US Class Current: 514/567
• CPC Class Codes: C07D 239/91 with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function by contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize hedgehog activity.

Claims

1. A method for inhibiting hyperproliferation of a cell, comprising contacting the cell with a compound in a sufficient amount to inhibit the hyperproliferation, wherein the compound is an organic molecule represented by the general formula (II):

2. The method of claim 1, wherein the cell has a hedgehog gain-of-function phenotype.

3. The method of claim 1, wherein the compound is administered to a patient as part of a therapeutic or cosmetic application.

4. The method of claim 3, wherein the therapeutic or cosmetic application is selected from-regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primative gut, regulation of hematopoietic function, or regulation of skin and hair growth.

5. The method of claim 1, wherein X is NR₈.

6. The method of claim 5, wherein R₈ in X represents a substituted alkyl.

7. The method of claim 6, wherein R₈ in X represents an alkyl substituted with a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.

8. The method of claim 1, wherein Y is C═

O.

9. The method of claim 1, wherein Z is a direct bond.

10. The method of claim 1, wherein L adjacent to R₂ is absent.

11. The method of claim 1, wherein L adjacent to X is absent or is —

(CH₂)_n-alkyl.

12. The method of claim 1, wherein R₂ is substituted or unsubstituted aryl.

13. The method of claim 1, wherein R₁ is substituted or unsubstituted aryl or aralkyl.

57. The method of claim 1, wherein the compound inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

58. The method of claim 1, wherein the compound inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

59. The method of claims 1, wherein the compound inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 nM or less.

14. A method for treating cancer in a patient, comprising administering to the patient a compound having a structure of general formula (II):

15. The method of claim 14, wherein said cancer is basal cell carcinoma.

16. The method of claim 14, wherein said cancer is squamous cell carcinoma, carcinosarcoma, adenocystic carcinoma, epidemoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, epidemoidoma, pancreatic cancer, a tumor related to Gorlin'"'"'s syndrome, a tumor evidenced in pct knock-out mice, a tumor resulting from gli-I amplification, a tumor connected with ptc homolog TRC8, an Ext-1-related tumor, an Shh-induced tumor, breast cancer, urogenital cancer, adrenal cancer, gastrointestinal cancer, malignant glioma, meningioma, a neuroectodermal tumor, an ependymoma, pineoblastoma, or keratoacanthoma.

19. The method of claim 14, wherein R₁ represents a substituted or unsubstituted aryl or heteroaryl group.

20. The method of claim 14, wherein W is a substituted or unsubstituted benzo or pyrido ring.

21. The method of claim 19, wherein W is a substituted or unsubstituted benzo or pyrido ring.

22. The method of claim 14, wherein R₂ represents a lower alkyl, substituted or unsubstituted aryl or heteroaryl group.

23. The method of claim 19, wherein R₂ represents a lower alkyl, substituted or unsubstituted aryl or heteroaryl group.

24. The method of claim 21, wherein R₂ represents a lower alkyl, substituted or unsubstituted aryl or heteroaryl group.

26. The method of claim 14, wherein R₈, independently for each occurrence, is selected from H and lower alkyl.

27. The method of claim 19, wherein R₈, independently for each occurrence, is selected from H and lower alkyl.

28. The method of claim 21, wherein R₈, independently for each occurrence, is selected from H and lower alkyl.

29. The method of claim 24, wherein R₈, independently for each occurrence, is selected from H and lower alkyl.

31. The method of claim 14, wherein X-Y-Z taken together represents a urea or an amide.

32. The method of claim 19, wherein X-Y-Z taken together represents a urea or an amide.

33. The method of claim 21, wherein X-Y-Z taken together represents a urea or an amide.

34. The method of claim 24, wherein X-Y-Z taken together represents a urea or an amide.

35. The method of claim 29, wherein X-Y-Z taken together represents a urea or an amide.

38. The method of claim 14, wherein X represents a diazacarbocycle.

39. The method of claim 19, wherein X is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond;

Y is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

; and

Z is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond, such that at least one of X and Z is present.

40. The method of claim 39, wherein Y is selected from —

C(═

O)— and

—

C(═

S)—

.

41. The method of claim 39, wherein Z is selected from —

N(R₈)—

, —

O—

, and —

S—

.

42. The method of claim 40, wherein Z is selected from —

N(R₈)—

, —

O—

, and —

S—

.

43. The method of claim 14, wherein L adjacent to R₁ is absent, and L adjacent to X is a substituted or unsubstituted methylene.

44. The method of claim 19, wherein L adjacent to R₁ is absent, and L adjacent to X is a substituted or unsubstituted methylene.

45. The method of claim 21, wherein L adjacent to R₁ is absent, and L adjacent to X is a substituted or unsubstituted methylene.

46. The method as of claim 24, wherein L adjacent to R₁ is absent, and L adjacent to X is a substituted or unsubstituted methylene.

47. The method of claim 29, wherein L adjacent to R₁ is absent, and L adjacent to X is a substituted or unsubstituted methylene.

48. The method of claim 35, wherein L adjacent to R₁ is absent, and L adjacent to X is a substituted or unsubstituted methylene.

50. The method of claim 21, wherein L adjacent to R₁ is absent, and L adjacent to X is a substituted or unsubstituted methylene.

53. The method of claim 39, wherein p, individually for each occurrence, represents an integer in the range of 0 to 3

55. The method of claim 53, wherein n, individually for each occurrence, represents an integer in the range of 0 to 5.

17. A method for inhibiting hair growth in an animal, comprising administering to the animal a compound having a structure of general formula (II):

18. The method of claim 17, wherein the compound is administered topically.

25. The method of claim 17, wherein R₂ represents a substituted or unsubstituted aryl or heteroaryl group.

30. The method of claim 25, wherein R₈, independently for each occurrence, is selected from H and lower alkyl.

36. The method of claim 17, wherein X-Y-Z taken together represents a urea or an amide.

37. The method of claim 25, wherein X-Y-Z taken together represents a urea or an amide.

49. The method of claim 17, wherein L adjacent to R₁ is absent, and L adjacent to X is a substituted or unsubstituted methylene.

51. The method of claim 17, wherein X is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond;

Y is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

; and

Z is selected from —

N(R₈)—

, —

O—

, —

S—

, and a direct bond, such that at least one of X and Z is present.

52. The method of claim 25, wherein X-Y-Z taken together represents a urea or an amide.

54. The method of claim 51, wherein p, individually for each occurrence, represents an integer in the range of 0 to 3

56. The method of claim 54, wherein n, individually for each occurrence, represents an integer in the range of 0 to 5.