Mediators of hedgehog signaling pathways, compositions and uses related thereto

• US 7,300,929 B2
• Filed: 04/04/2003
• Issued: 11/27/2007
• Est. Priority Date: 10/14/1999
• Status: Expired due to Fees

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Price, Stephen, Boyd, Edward Andrew, Rubin, Lee L., Guicherit, Oivin, Baxter, Anthony David
• Primary Examiner(s): HUI, SAN MING R
• Application Number:
  US10/407,551
• Publication Number:
  US 20040023949A1
• Time in Patent Office: 1,698 Days
• Field of Search: 514/423, 514/424
• US Class Current: 514/218
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: C07K 14/43581 from Drosophila
• CPC Class Codes: C07K 14/461 from fish
• CPC Class Codes: C07K 14/465 from birds
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 16/18 against material from animals or humans

Abstract

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising 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 smoothened or hedgehog activity.

Claims

1. A method for treating a basal cell carcinoma or lung cancer in a patient, comprising administering to the patient a compound of formula (I):

2. The method of claim 1, wherein Y and Z each represent O.

3. The method of claim 1, wherein the sum of q and r is less than 4.

4. The method of claim 1, wherein D represents an aralkyl- or heteroaralkyl-substituted amine.

5. The method of claim 1, wherein R₁ represents a branched alkyl, a cycloalkyl, or a cycloalkylalkyl.

6. The method of claim 1, wherein L attached to R₁ represents O, S, or NR₈.

7. The method of claim 1, wherein E is NR₈.

8. The method of claim 1, wherein X is included in a ring.

9. The method of claim 1, wherein R₄LX includes a cyclic amine.

10. The method of claim 1, wherein the compound inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 μ

M or less.

11. The method of claim 1, wherein the compound inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 nM or less.

22. The method of claim 1, wherein the method is for treating a basal cell carcinoma.

40. The method of any one of claims 1, 12, 24, or 31, wherein the basal cell carcinoma or lung cancer is associated with a tumor.

12. A method for treating cancer a basal cell carcinoma or lung cancer in a patient, comprising administering to the patient a compound of formula (II):

13. The method of claim 12, wherein Y and Z each represent O.

14. The method of claim 12, wherein the sum of q, r, and s is less than 5.

15. The method of claim 12, wherein at least one of R₁, R₂, and R₃ includes an aryl group.

16. The method of claim 12, wherein R₄LX includes a cyclic diamine.

17. The method of claim 12, wherein X is included in a diazacarbocycle.

18. The method of claim 12, wherein R₁ represents a branched alkyl, a cycloalkyl, or a cycloalkylalkyl.

19. The method of claim 12, wherein L attached to R₁ represents O, S, or NR₈.

20. The method of claim 12, wherein the compound inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 μ

M or less.

21. The method of claim 12, wherein the compound inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 nM or less.

23. The method of claim 12, wherein the method is for treating a basal cell carcinoma.

24. A method for treating cancer a basal cell carcinoma or lung cancer in a patient, comprising administering to the patient a compound of formula (III):

25. The method of claim 24, wherein the sum of q and r is less than 4.

26. The method of claim 24, wherein R₁ represents a branched alkyl, a cycloalkyl, or a cycloalkylalkyl.

27. The method of claim 24, wherein R₄LX includes a cyclic amine.

28. The method of claim 24, wherein the compound inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 mM or less.

29. The method of claim 24, wherein the compound inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 μ

M or less.

30. The method of claim 24, wherein the compound inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 nM or less.

34. The method of claim 24, wherein R₄LX includes a cyclic amine.

38. The method of claim 24, wherein the method is for treating a basal cell carcinoma.

31. A method for treating cancer a basal cell carcinoma or lung cancer in a patient, comprising administering to the patient a compound of formula (IV):

32. The method of claim 31, wherein R₁ represents a branched alkyl, a cycloalkyl, or a cycloalkylalkyl.

33. The method of claim 31, wherein at least one of R₁, R₂, and R₃ includes an aryl group.

35. The method of claim 31, wherein X is part of a diazacarbocycle.

36. The method of claim 31, wherein the compound inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 μ

M or less.

37. The method of claim 31, wherein the compound inhibits ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 nM or less.

39. The method of claim 31, wherein the method is for treating a basal cell carcinoma.