Inhibitors of hedgehog signaling pathways, compositions and uses related thereto

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.

1 - 26 . (canceled) 
     
     
         27 . A method for inhibiting activation of a hedgehog-patched pathway in a patient diagnosed with cancer, comprising administering to the patient a composition comprising a pharmaceutically acceptable excipient and a sufficient amount of means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway. 
     
     
         28 . The method of  claim 27 , wherein the cancer is basal cell carcinoma, medulloblastoma, squamous cell carcinoma, carcinosarcoma, adenocystic carcinoma, epidermoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, or an epidermoidoma. 
     
     
         29 . The method of  claim 27 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway is jervine or cyclopamine. 
     
     
         30 . The method of  claim 27 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED 50  of 1 mM or less. 
     
     
         31 . The method of  claim 30 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED 50  of 1 μM or less. 
     
     
         32 . The method of  claim 31 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED 50  of 1 nM or less. 
     
     
         33 . An in vitro method for inhibiting proliferation of a cancer cell, comprising contacting the cell in vitro with means for binding smoothened and inhibiting activation of the hedgehog-patched pathway. 
     
     
         34 . The method of  claim 33 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway is jervine or cyclopamine. 
     
     
         35 . The method of  claim 33 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED 50  of 1 mM or less. 
     
     
         36 . The method of  claim 35 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED 50  of 1 μM or less. 
     
     
         37 . A method for inhibiting mitotic cell proliferation associated with a cancer in an animal, comprising administering to the animal a composition comprising a pharmaceutically acceptable excipient and a sufficient amount of means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway. 
     
     
         38 . The method of  claim 37 , wherein the cancer is basal cell carcinoma, medulloblastoma, squamous cell carcinoma, carcinosarcoma, adenocystic carcinoma, epidermoid carcinoma, nasopharyngeal carcinoma, renal cell carcinoma, papilloma, or an epidermoidoma. 
     
     
         39 . The method of  claim 37 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway is jervine or cyclopamine. 
     
     
         40 . The method of  claim 37 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED 50  of 1 mM or less. 
     
     
         41 . The method of  claim 40 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED 50  of 1 μM or less. 
     
     
         42 . The method of  claim 41 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED 50  of 1 nM or less. 
     
     
         43 . A method for inhibiting unwanted hair growth or inhibiting spermatogenesis in an animal, comprising administering to the patient a composition comprising a pharmaceutically acceptable excipient and a sufficient amount of means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway. 
     
     
         44 . The method of  claim 43 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway is jervine or cyclopamine. 
     
     
         45 . The method of  claim 43 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED 50  of 1 mM or less. 
     
     
         46 . The method of  claim 45 , wherein the means for binding to smoothened and inhibiting activation of the hedgehog-patched pathway inhibits hedgehog-mediated signal transduction with an ED 50  of 1 μM or less.