Inhibitors of hedgehog signaling pathways, compositions and uses related thereto

• US 8,097,632 B2
• Filed: 08/20/2007
• Issued: 01/17/2012
• Est. Priority Date: 04/09/1998
• Status: Expired due to Fees

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Beachy, Philip A., Porter, Jeffery A., Cooper, Michael K.
• Primary Examiner(s): Badio, Barbara P
• Application Number:
  US11/894,712
• Publication Number:
  US 20080058298A1
• Time in Patent Office: 1,611 Days
• Field of Search: 514/278
• 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 available 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 therapeutically treating cancer in a patient diagnosed with cancer,

wherein the cancer is basal cell carcinoma, medulloblastoma, squamous cell carcinoma, carcinosarcoma, adenocystic carcinoma, epidermoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, a papilloma, an epidermoidoma, a glioma, meningioma, a neuroectodermal tumor, an ependymoma, pineoblastoma, hemangioma, pancreatic cancer, adenocarcinoma, rhabdomyosarcoma, glioblastoma, sarcoma, thyroid carcinoma, bone cancer, lung cancer, chondrosarcoma, breast cancer, urogenital cancer, kidney cancer, bladder cancer, ureter cancer, prostate cancer, adrenal cancer, gastrointestinal cancer, stomach cancer, intestinal cancer, keratoacanthoma, or malignant hepatoma,

comprising administering to the patient a steroidal alkaloid represented in general Formula II or a homo-derivative thereof:

2. The method of claim 1, wherein:

R₂ and R₃, for each occurrence, is an —

OH, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈;

R₄, for each occurrence, is hydrogen, or represents —

OH, ═

O, alkyl, —

O-alkyl, —

C(O)-alkyl, or —

C(O)—

R₈; and

R₆, R₇, and R′

₇ each independently represent, hydrogen, alkyls, alkenyls, alkynyls, amines, imines, amides, carbonyls, carboxyls, carboxamides, ethers, thioethers, esters, or —

(CH₂)_m—

R₈, or

R₇, and R′

₇ taken together form a furanopiperidine, a pyranopiperidine, a quinoline, an indole, a pyranopyrrole, a naphthyridine, a thiofuranopiperidine, or a thiopyranopiperidine.

3. The method of claim 1, wherein the steroidal alkaloid is represented in the following general formula a homo-derivative thereof:

4. The method of claim 1, wherein the steroidal alkaloid does not interfere with the biological activity of aldosterone, androstane, androstene, androstenedione, androsterone, cholecalciferol, cholestane, cholic acid, corticosterone, cortisol, cortisol acetate, cortisone, cortisone acetate, deoxycorticosterone, digitoxigenin, ergocalciferol, ergosterol, estradiol-17-α

, estradiol-17-β

, estriol, estrane, estrone, hydrocortisone, lanosterol, lithocholic acid, mestranol, β

-methasone, prednisone, pregnane, pregnenolone, progesterone, spironolactone, testosterone, and triamcinolone.

5. The method of claim 1, wherein the steroidal alkaloid does not specifically bind a nuclear hormone receptor.

6. The method of claim 1, wherein the steroidal alkaloid does not specifically bind estrogen or testosterone receptors.

7. The method of claim 1, wherein the steroidal alkaloid has no estrogenic activity at therapeutic concentrations.

8. The method of claim 1, wherein the steroidal alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

9. The method of claim 1, wherein the steroidal alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

10. The method of claim 1, wherein the steroidal alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 nM or less.

11. The method of claim 1, wherein the cancer is a basal cell carcinoma, chondrosarcoma, or pancreatic cancer.

12. The method of claim 2, wherein R₇ and R′

₇ taken together form a furanopiperidine.

13. The method of claim 3, wherein the carbon to which R₅ is connected is part of a double bond and R₅ is absent.

14. The method of claim 3, wherein R₃ is methyl.

15. The method of claim 3, wherein R₄ is hydrogen.

16. The method of claim 3, wherein R₆ is methyl.

17. The method of claim 3, wherein R₂₂ is methyl.

18. The method of claim 3, wherein one occurrence of R₉ is methyl and in a 1,3-relationship to the piperidine ring nitrogen.

19. The method of claim 3, wherein

the carbon to which R₅ is connected is part of a double bond and R₅ is absent;

R₃ is methyl;

R₄ is hydrogen;

R₆ is methyl;

R₂₂ is methyl; and

one occurrence of R₉ is methyl and in a 1,3-relationship to the piperidine ring nitrogen.