INHIBITORS OF HEDGEHOG SIGNALING PATHWAYS, COMPOSITIONS AND USES RELATED THERETO

• US 20100273818A1
• Filed: 01/05/2010
• Published: 10/28/2010
• Est. Priority Date: 04/09/1998
• Status: Abandoned Application

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Porter, Jeffrey A., Cooper, Michael K., Beachy, Philip A.
• Application Number:
  US12/652,134
• Publication Number:
  US 20100273818A1
• Time in Patent Office: Days
• US Class Current: 514/278
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/4355 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention makes availables assays and reagents inhibiting paracrine and/or autocrine signals produced by a hedgehog protein or aberrant activation of a hedgehog signal transduction pathway, e.g., which involve the use of a steroidal alkaloid or other small molecule.

Claims

1-26. -26. (canceled)

27. A method for inhibiting activation of a hedgehog-patched pathway in a patient diagnosed with cancer, comprising administering to the patient a composition comprising a pharmaceutically acceptable excipient and a sufficient amount of means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway.

28. The method of claim 27, wherein the cancer is basal cell carcinoma, medulloblastoma, squamous cell carcinoma, carcinosarcoma, adenocystic carcinoma, epidermoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, or an epidermoidoma.

29. The method of claim 27, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway is jervine or cyclopamine.

30. The method of claim 27, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

31. The method of claim 30, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

32. The method of claim 31, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 nM or less.

33. An in vitro method for inhibiting proliferation of a cancer cell, comprising contacting the cell in vitro with means for binding smoothened and inhibiting activation of the hedgehog-patched pathway.

34. The method of claim 33, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway is jervine or cyclopamine.

35. The method of claim 33, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

36. The method of claim 35, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

37. A method for inhibiting mitotic cell proliferation associated with a cancer in an animal, comprising administering to the animal a composition comprising a pharmaceutically acceptable excipient and a sufficient amount of means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway.

38. The method of claim 37, wherein the cancer is basal cell carcinoma, medulloblastoma, squamous cell carcinoma, carcinosarcoma, adenocystic carcinoma, epidermoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, or an epidermoidoma.

39. The method of claim 37, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway is jervine or cyclopamine.

40. The method of claim 37, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

41. The method of claim 40, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

42. The method of claim 41, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 nM or less.

43. A method for inhibiting unwanted hair growth or inhibiting spermatogenesis in an animal, comprising administering to the patient a composition comprising a pharmaceutically acceptable excipient and a sufficient amount of means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway.

44. The method of claim 43, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway is jervine or cyclopamine.

45. The method of claim 43, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

46. The method of claim 45, wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.