Inhibitors of hedgehog signaling pathways, compositions and uses related thereto

• US 9,427,431 B2
• Filed: 02/01/2012
• Issued: 08/30/2016
• Est. Priority Date: 04/09/1998
• Status: Expired due to Fees

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Porter, Jefferey A., Beachy, Philip A., Cooper, Michael K.
• Primary Examiner(s): Badio, Barbara P
• Application Number:
  US13/364,121
• Publication Number:
  US 20120183603A1
• Time in Patent Office: 1,672 Days
• Field of Search: 514/224.2
• US Class Current: 1/1
• 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. A method of therapy for a human subject having a basal cell carcinoma tumor,

comprising administering to the subject a therapeutically effective amount of a medicament comprising cyclopamine and a pharmaceutically acceptable carrier,

wherein in said tumor smoothened-dependent hedgehog signaling is utilized for inhibition of apoptosis, and

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.

2. A method of claim 1 wherein said medicament is in the form of a pharmaceutical composition for topical administration and is applied 4 or more times a day.

3. A method of claim 2 wherein said medicament is in the form of a cream.

4. A method of therapy for a human subject having a tumor in which smoothened-dependent hedgehog signaling is used for inhibition of apoptosis and selective inhibition of differentiation, comprising administering to the subject a therapeutically effective amount of a medicament comprising cyclopamine and a pharmaceutically acceptable carrier, wherein said amount of cyclopamine selectively inhibits smoothened-dependent hedgehog signaling in said tumor and induces apoptosis in and inhibits proliferation of said tumor.

5. A method of claim 4 wherein said amount of cyclopamine is not toxic to the subject and causes reduced side effects.

6. A method of claim 4 wherein said medicament is a pharmaceutical composition for topical or systemic administration.

7. A method of claim 6 wherein the composition for systemic administration is in the form of an aqueous solution.

8. A method of claim 6 wherein the composition is administered by injection.

9. A method of claim 6 wherein the pharmaceutical composition achieves controlled release.

10. A method of claim 6 wherein the pharmaceutical composition is in the form of a patch or a transdermal patch.

11. A method of claim 6 wherein the pharmaceutical composition is in the form of a cream or ointment or gel or hydrogel.

12. A method of claim 4 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.

13. 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, wherein smoothened-dependent hedgehog signaling is also used for selective inhibition of differentiation in said tumor, wherein said medicament is a pharmaceutical composition for topical or systemic administration, wherein the composition is in the form of a liposome.