Mediators of hedgehog signaling pathways, compositions and uses related thereto

Abstract

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function by contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize hedgehog activity.

1 . A compound which inhibits the hedgehog pathway in a normal cell and does not inhibit the hedgehog pathway in a patched-null cell.  
     
     
         2 . The compound of  claim 1 , wherein the compound has a molecular weight less than about 2000 amu.  
     
     
         3 . The compound of  claim 1 , wherein the compound has a molecular weight less than about 1000 amu.  
     
     
         4 . The compound of  claim 1 , wherein the compound causes a decrease in gli transcription of at least about 5% relative to an untreated control cell.  
     
     
         5 . The compound of  claim 1 , wherein the compound causes a decrease in gli transcription of at least about 10% relative to an untreated control cell.  
     
     
         6 . The compound of  claim 1 , wherein the compound causes a decrease in gli transcription of at least about 20% relative to an untreated control cell.  
     
     
         7 . The compound of  claim 1 , wherein the compound binds to patched.  
     
     
         8 . The compound of  claim 1 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 1 μM.  
     
     
         9 . The compound of  claim 1 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 100 nM.  
     
     
         10 . The compound of  claim 1 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 10 nM.  
     
     
         11 . The compound of  claim 2 , wherein the compound causes a decrease in gli transcription of at least about 5% relative to an untreated control cell.  
     
     
         12 . The compound of  claim 2 , wherein the compound causes a decrease in gli transcription of at least about 10% relative to an untreated control cell.  
     
     
         13 . The compound of  claim 2 , wherein the compound causes a decrease in gli transcription of at least about 20% relative to an untreated control cell.  
     
     
         14 . The compound of  claim 2 , wherein the compound binds to patched.  
     
     
         15 . The compound of  claim 2 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 1 μM.  
     
     
         16 . The compound of  claim 2 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 100 μM.  
     
     
         17 . The compound of  claim 2 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 10 nM.  
     
     
         18 . The compound of  claim 4 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 1 μM.  
     
     
         19 . The compound of  claim 4 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 100 nM.  
     
     
         20 . The compound of  claim 4 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 10 nM.  
     
     
         21 . The compound of  claim 11 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 1 μM.  
     
     
         22 . The compound of  claim 11 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 100 nM.  
     
     
         23 . The compound of  claim 11 , wherein the compound inhibits the hedgehog pathway with an IC 50  less than about 10 nM.  
     
     
         24 . The compound of  claim 2 , wherein the compound increases PKA activity in a cell by a factor of at least about 2 relative to an untreated control cell.  
     
     
         25 . The compound of  claim 2 , wherein the compound increases PKA activity in a cell by a factor of at least about 3 relative to an untreated control cell.  
     
     
         26 . The compound of  claim 2 , wherein the compound increases PKA activity in a cell by a factor of at least about 5 relative to an untreated control cell.  
     
     
         27 . The compound of  claim 8 , wherein the compound increases PKA activity in a cell by a factor of at least about 2 relative to an untreated control cell.  
     
     
         28 . The compound of  claim 8 , wherein the compound increases PKA activity in a cell by a factor of at least about 3 relative to an untreated control cell.  
     
     
         29 . The compound of  claim 8 , wherein the compound increases PKA activity in a cell by a factor of at least about 5 relative to an untreated control cell.  
     
     
         30 . A compound which inhibits activation of the hedgehog pathway by a hedgehog protein, but does not inhibit activation of the hedgehog pathway by the following compound: