Regulators of the hedgehog pathway, compositions and uses related thereto

• US 7,998,946 B2
• Filed: 03/28/2008
• Issued: 08/16/2011
• Est. Priority Date: 10/13/1999
• Status: Expired due to Fees

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Taipale, Anssi Jussi Nikolai, Beachy, Philip A., Chen, James K.
• Primary Examiner(s): Lewis; Patrick
• Application Number:
  US12/079,776
• Publication Number:
  US 20080255059A1
• Time in Patent Office: 1,236 Days
• Field of Search: None
• US Class Current: 514/79
• 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 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 : for non-specific disorders of the connective tissue
• 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 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/00 : Drugs for disorders of the senses
• CPC Class Codes: A61P 27/12 : for cataracts
• 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: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: C07J 69/00 : Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom

Abstract

The present invention makes available, inter alia, methods and reagents for modulating smoothened-dependent pathway activation. In certain embodiments, the subject methods can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function mutations.

Claims

1. A method for inhibiting mitotic cell proliferation in an animal comprising administering to the animal a veratrum-type alkaloid, wherein the veratrum-type alkaloid includes a nitrogen-containing ring comprising a tertiary amine having an extraannular substituent on the nitrogen.

2. The method of claim 1, wherein the mitotic cell proliferation is associated with a cancer.

3. The method of claim 1, wherein the extraannular substituent is hydrophobic.

4. The method of claim 1, wherein the extraannular substituent incorporates a substituted alkyl.

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

20. The method of claim 2, wherein the cancer is selected from a basal cell carcinoma, medulloblastoma, squamous cell carcinoma, carcinosarcoma, adenocystic carcinoma, epidermoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, and an epidermoidoma.

21. The method of claim 1, wherein the extraannular substituent comprises a combination of alkyl, amido, acylamino, ketone, ester, ether, halogen, alkenyl, alkynyl, aryl, aralkyl, or urea groups.

22. The method of claim 1, wherein the extraannular substituent incorporates an aryl, heteroaryl, carbocyclyl, heterocyclyl, or polycyclyl group.

23. The method of claim 1, wherein the extraannular substituent incorporates a polycyclyl group selected from biotin, a zwitterionic complex of boron, and a steroidal polycycle.

24. The method of claim 4, wherein the substituted alkyl is substituted with a group selected from aryl, aralkyl, heteroaryl, heteroaralkyl, amide, acylamino, carbonyl, ester, carbamate, urea, ketone, sulfonamide, carbocyclyl, heterocyclyl, polycyclyl, ether, halogen, alkenyl, and alkynyl.

25. The method of claim 24, wherein the substituted alkyl is substituted with an acylamino.

26. The method of claim 5, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

27. The method of claim 26, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 nM or less.

6. A method for inhibiting activation of a hedgehog-patched pathway in a patient diagnosed with a hyperproliferative disorder comprising administering to the patient a veratrum-type alkaloid, wherein the veratrum-type alkaloid includes a nitrogen-containing ring comprising a tertiary amine having an extraannular substituent on the nitrogen.

7. The method of claim 6, wherein the hyperproliferative disorder is associated with a cancer.

8. The method of claim 6, wherein the extraannular substituent is hydrophobic.

9. The method of claim 6, wherein the extraannular substituent incorporates a substituted alkyl.

10. The method of claim 6, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

28. The method of claim 7, wherein the cancer is selected from a basal cell carcinoma, medulloblastoma, squamous cell carcinoma, carcinosarcoma, adenocystic carcinoma, epidermoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, and an epidermoidoma.

29. The method of claim 6, wherein the extraannular substituent comprises a combination of alkyl, amido, acylamino, ketone, ester, ether, halogen, alkenyl, alkynyl, aryl, aralkyl, or urea groups.

30. The method of claim 6, wherein the extraannular substituent incorporates an aryl, heteroaryl, carbocyclyl, heterocyclyl, or polycyclyl group.

31. The method of claim 6, wherein the extraannular substituent incorporates a polycyclyl group selected from biotin, a zwitterionic complex of boron, and a steroidal polycycle.

32. The method of claim 9, wherein the substituted alkyl is substituted with a group selected from aryl, aralkyl, heteroaryl, heteroaralkyl, amide, acylamino, carbonyl, ester, carbamate, urea, ketone, sulfonamide, carbocyclyl, heterocyclyl, polycyclyl, ether, halogen, alkenyl, and alkynyl.

33. The method of claim 32, wherein the substituted alkyl is substituted with an acylamino.

34. The method of claim 10, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

35. The method of claim 34, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 nM or less.

11. A method for inhibiting unwanted hair growth or inhibiting spermatogenesis in a patient comprising administering to the patient a veratrum-type alkaloid, wherein the veratrum-type alkaloid includes a nitrogen-containing ring comprising a tertiary amine having an extraannular substituent on the nitrogen.

12. The method of claim 11, wherein the extraannular substituent is hydrophobic.

13. The method of claim 11, wherein the extraannular substituent incorporates a substituted alkyl.

14. The method of claim 11, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

36. The method of claim 11, wherein the extraannular substituent comprises a combination of alkyl, amido, acylamino, ketone, ester, ether, halogen, alkenyl, alkynyl, aryl, aralkyl, or urea groups.

37. The method of claim 11, wherein the extraannular substituent incorporates an aryl, heteroaryl, carbocyclyl, heterocyclyl, or polycyclyl group.

38. The method of claim 11, wherein the extraannular substituent incorporates a polycyclyl group selected from biotin, a zwitterionic complex of boron, and a steroidal polycycle.

39. The method of claim 13, wherein the substituted alkyl is substituted with a group selected from aryl, aralkyl, heteroaryl, heteroaralkyl, amide, acylamino, carbonyl, ester, carbamate, urea, ketone, sulfonamide, carbocyclyl, heterocyclyl, polycyclyl, ether, halogen, alkenyl, and alkynyl.

40. The method of claim 39, wherein the substituted alkyl is substituted with an acylamino.

41. The method of claim 14, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

42. The method of claim 41, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 nM or less.

15. An in vitro method for inhibiting mitotic cell proliferation in a cell, comprising contacting the cell in vitro with a veratrum-type alkaloid, wherein the veratrum-type alkaloid includes a nitrogen-containing ring comprising a tertiary amine having an extraannular substituent on the nitrogen.

16. The method of claim 15, wherein the cell proliferation is associated with a cancer.

17. The method of claim 15, wherein the extraannular substituent is hydrophobic.

18. The method of claim 15, wherein the extraannular substituent incorporates a substituted alkyl.

19. The method of claim 15, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 mM or less.

43. The method of claim 16, wherein the cancer is selected from a basal cell carcinoma, medulloblastoma, squamous cell carcinoma, carcinosarcoma, adenocystic carcinoma, epidermoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, and an epidermoidoma.

44. The method of claim 15, wherein the extraannular substituent comprises a combination of alkyl, amido, acylamino, ketone, ester, ether, halogen, alkenyl, alkynyl, aryl, aralkyl, or urea groups.

45. The method of claim 15, wherein the extraannular substituent incorporates an aryl, heteroaryl, carbocyclyl, heterocyclyl, or polycyclyl group.

46. The method of claim 15, wherein the extraannular substituent incorporates a polycyclyl group selected from biotin, a zwitterionic complex of boron, and a steroidal polycycle.

47. The method of claim 18, wherein the substituted alkyl is substituted with a group selected from aryl, aralkyl, heteroaryl, heteroaralkyl, amide, acylamino, carbonyl, ester, carbamate, urea, ketone, sulfonamide, carbocyclyl, heterocyclyl, polycyclyl, ether, halogen, alkenyl, and alkynyl.

48. The method of claim 47, wherein the substituted alkyl is substituted with an acylamino.

49. The method of claim 19, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 μ

M or less.

50. The method of claim 49, wherein the veratrum-type alkaloid inhibits hedgehog-mediated signal transduction with an ED₅₀ of 1 nM or less.