Regulators of the hedgehog pathway, compositions and uses related thereto

• US 9,440,988 B2
• Filed: 02/01/2012
• Issued: 09/13/2016
• 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., Chen, James K., Taipale, Anssi Jussi Nikolai
• Primary Examiner(s): Olson, Eric
• Application Number:
  US13/363,934
• Publication Number:
  US 20120135066A1
• Time in Patent Office: 1,686 Days
• Field of Search: None
• US Class Current: 1/1
• 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 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,

wherein in said tumor smoothened-dependent hedgehog signaling is utilized for inhibition of apoptosis, and wherein said medicament is administered in a dose that induces apoptosis in said tumor, causes decrease of size of the tumor, and selectively inhibits smoothened-dependent hedgehog signaling in said tumor.

13. 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.

14. A method of claim 13 wherein said medicament is in the form of a cream.

2. A method for the treatment of a human subject having a tumor in which smoothened-dependent hedgehog signaling is used, comprising

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

wherein in said tumor smoothened-dependent hedgehog signaling is utilized for inhibition of apoptosis, and said medicament is administered in a dose that induces apoptosis in said tumor, causes decrease of size of the tumor and selectively inhibits smoothened-dependent hedgehog signaling in said tumor.

3. A method of claim 2 wherein smoothened-dependent hedgehog signaling is also used for inhibition of differentiation and said dose is sufficient to induce differentiation in said tumor.

4. A method of claim 2 wherein said amount of cyclopamine is not toxic to the subject.

5. A method of claim 3 wherein said amount of cyclopamine is not toxic to the subject.

6. A method of claim 3 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 systemically 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 2 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.

26. A method of claim 6 wherein said medicament is in the form of a cream or a liposome.

15. A method for treatment of a human subject having a tumor, comprising

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

administering to the subject a medicament comprising cyclopamine or a pharmaceutically acceptable salt thereof,

wherein said medicament is administered in a dose that is sufficient to induce apoptosis of said tumor cells and causes decrease of size of the tumor.

16. A method of claim 15 wherein said tumor is basal cell carcinoma.

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

18. A method of claim 17 wherein said medicament is a pharmaceutical composition for topical or systemic administration.

19. A method of claim 18 wherein the composition for systemic administration is in the form of an aqueous solution.

20. A method of claim 18 wherein the composition is in the form of a liposome.

21. A method of claim 18 wherein the composition is administered by injection.

22. A method of claim 18 wherein the pharmaceutical composition achieves controlled release.

23. A method of claim 18 wherein the pharmaceutical composition is in the form of a patch or a transdermal patch.

24. A method of claim 18 wherein the pharmaceutical composition is in the form of a cream or ointment or gel or hydrogel.

25. A method of claim 17 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.