Regulators of the hedgehog pathway, compositions and uses related thereto

• US 6,291,516 B1
• Filed: 10/14/1999
• Issued: 09/18/2001
• Est. Priority Date: 01/13/1999
• Status: Expired due to Term

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Dudek, Henryk, Ji, Benxiu
• Primary Examiner(s): KRASS, FREDERICK F
• Application Number:
  US09/417,564
• Time in Patent Office: 705 Days
• Field of Search: 514/455, 514/47, 514/169, 514/222.5, 514/226.2, 514/236.2, 514/257, 514/258, 514/260, 514/261, 514/262, 514/263, 514/266, 514/275, 514/280, 514/311, 514/314, 514/317, 514/327, 514/331, 514/346, 514/347, 514/397, 514/415, 514/420, 514/424, 514/470, 514/473, 514/478, 514/479, 514/523, 514/530, 514/535, 514/537, 514/538, 514/573, 514/605, 514/617, 514/620, 514/642, 514/651, 514/652, 514/653, 514/863, 424/236.1, 424/240.1, 600/562
• US Class Current: 514/455
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/585 containing lactone rings, e.g. oxandrolone, bufalin
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

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 a cell with a compound, such as a polypeptide or small molecule in an amount sufficient to control the aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity. The present invention further makes available methods and reagents for ameliorating the consequences of hedgehog loss-of-function, ptc gain-of-function, or smoothened loss-of-function comprising contacting a cell with a compound, such as a polypeptide or small molecule, in an amount sufficient to ameliorate the In certain embodiments, the subject compounds, e.g., a cAMP analog, adenylate cyclase agonist, or cAMP phosphodiesterase inhibitor, regulate cAMP levels, which in turn modulates activity of the hedgehog pathway.

Claims

1. A method for treating a condition characterized by an altered growth state of a tissue in a patient, comprising

(i) detecting aberrant activation of a hedgehog pathway in the tissue, and

(ii) contacting the cell with a composition including at least one cAMP agonist.

2. The method of claim 1, wherein at least one cAMP agonist activates adenylate cyclase.

3. The method of claim 1, wherein at least one cAMP agonist is a cAMP analog.

4. The method of claim 1, wherein at least one cAMP agonist is a cAMP phosphodiesterase inhibitor.

5. The method of claim 1, wherein the composition inhibits ptc loss-of-function mediated signal transduction with an ED₅₀ of 1 mM or less.

6. The method of claim 1, wherein the composition inhibits hedgehog gain-of-function mediated signal transduction with an ED₅₀ of 1 nM or less.

7. The method of claim 1, wherein the composition inhibits smoothened gain-of-function mediated signal transduction with an ED₅₀ of 1 μ

M or less.

8. The method of claim 1, wherein the tissue is contacted with the composition in vitro.

9. The method of claim 1, wherein the tissue is contacted with the composition in vivo.

10. The method of claim 1, wherein the composition is administered as part of a therapeutic or cosmetic application.

11. The method of claim 10, wherein the therapeutic or cosmetic application is selected from the group consisting of 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 primitive gut, regulation of hematopoietic function, and regulation of skin and hair growth.

12. The method of claim 1, wherein the composition includes forskolin or a derivative thereof.

15. The method of claim 1, wherein the aberrant activation includes a ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function phenotype.

13. A method for treating or prophylacting against basal cell carcinoma, comprising administering a composition including a cAMP agonist to a patient in need thereof in an amount sufficient to inhibit progression of basal cell carcinoma.

14. A method for inhibiting an altered growth state of a cell, comprising

detecting aberrant activation of a hedgehog pathway in the cell;

and

contacting the cell with a cAMP agonist in an amount sufficient to inhibit the altered growth state of the cell.

16. The method of claim 14, wherein the aberrant activation includes a ptc loss-of-function, hedgehog gain-of-function, or smoothened gain-of-function phenotype.