INHIBITORS OF HEDGEHOG SIGNALING PATHWAYS, COMPOSITIONS AND USES RELATED THERETO

• US 20120183603A1
• Filed: 02/01/2012
• Published: 07/19/2012
• Est. Priority Date: 04/09/1998
• Status: Active Grant

• Current Assignee: Jeffrey A. Porter, Michael K. Cooper, Philip A. Beachy
• Original Assignee: Jeffrey A. Porter, Michael K. Cooper, Philip A. Beachy
• Inventors: Cooper, Michael K., Porter, Jeffrey A., BEACHY, Philip A.
• Granted Patent: US 9,427,431 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• 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 the treatment of a human subject having a basal cell carcinoma tumor,

comprising administering to the subject an effective amount of a medicament comprising cyclopamine.

28. A method of claim 27 wherein in said tumor smoothened-dependent hedgehog signaling is utilized for inhibition of apoptosis.

29. A method of claim 27 wherein said amount of cyclopamine selectively inhibits smoothened-dependent hedgehog signaling in said tumor.

30. A method of claim 28 wherein said amount of cyclopamine selectively inhibits smoothened-dependent hedgehog signaling in said tumor and is sufficient to induce apoptosis in said tumor and inhibits tumor cell proliferation.

49. A method of claim 27 wherein said medicament is in the form of a pharmaceutical composition for topical administration and is applied 4 or more times a day.

50. A method of claim 49 wherein said medicament is in the form of a cream.

31. A method for the treatment of a human subject having a tumor in which smoothened-dependent hedgehog signaling is used for inhibition of apoptosis, comprising administering to the subject an effective amount of a medicament comprising cyclopamine.

32. A method of claim 31 wherein said amount of cyclopamine selectively inhibits smoothened-dependent hedgehog signaling in said tumor.

33. A method of claim 31 wherein said amount of cyclopamine selectively inhibits smoothened-dependent hedgehog signaling in said tumor and induces apoptosis in and inhibits proliferation of said tumor.

34. A method of claim 31 comprising determining that smoothened-dependent hedgehog signaling is utilized for inhibition of apoptosis in said tumor.

35. A method of claim 33 comprising determining that smoothened-dependent hedgehog signaling is utilized for inhibition of apoptosis in said tumor.

36. A method of claim 31 wherein smoothened-dependent hedgehog signaling is also used for selective inhibition of differentiation in said tumor.

37. A method of claim 36 wherein said amount of cyclopamine inhibits smoothened-dependent hedgehog signaling in said tumor.

38. A method of claim 36 wherein said amount of cyclopamine inhibits smoothened-dependent hedgehog signaling in said tumor and induces apoptosis and differentiation in said tumor and inhibits tumor cell proliferation.

39. A method of claim 33 wherein said amount of cyclopamine is not toxic to the subject and causes reduced side effects.

40. A method of claim 38 wherein said amount of cyclopamine is not toxic to the subject and causes reduced side effects.

41. A method of claim 36 wherein said medicament is a pharmaceutical composition for topical or systemic administration.

42. A method of claim 41 wherein the composition for systemic administration is in the form of an aqueous solution.

43. A method of claim 41 wherein the composition is in the form of a liposome.

44. A method of claim 41 wherein the composition is administered by injection.

45. A method of claim 41 wherein the pharmaceutical composition achieves controlled release.

46. A method of claim 41 wherein the pharmaceutical composition is in the form of a patch or a transdermal patch.

47. A method of claim 41 wherein the pharmaceutical composition is in the form of a cream or ointment or gel or hydrogel.

48. A method of claim 31 wherein the tumor is a skin tumor and the medicament is in the form of a pharmaceutical composition for injection or topical or oral or parenteral administration.