Smoothened antagonism for the treatment of hedgehog pathway-related disorders

Abstract

The invention provides methods for modulating, e.g., antagonizing, the activity of the Hedgehog signaling pathway, and for treating Hedgehog related disorders such as cancers (e.g., medulloblastoma). In particular, the invention provides methods for inhibiting aberrant growth states resulting from phenotypes such as Ptch loss-of-function, Hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function by administering to a mammal combinations of Smoothened inhibitors (e.g., a compound of Formula I, Formula II, or Formula III, or any of the compounds listed herein or incorporated by reference) and cholesterol biosynthesis pathway inhibitors (e.g., statins), Gli inhibitors, and/or Phosphatidylinositol 3-kinase (PI3K) inhibitors.

What is claimed is: 
     
         1 . A method for treating a Hedgehog-related cancer in a patient in need thereof comprising administering to the patient a Smoothened inhibitor and a PI3 kinase inhibitor, wherein the Smoothened inhibitor is 2-methyl-4′-trifluoromethoxy-biphenyl-3-carboxylic acid [6-dimethyl-morpholin-4-yl)-pyridin-3-yl]amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide, 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the cancer is a medulloblastoma. 
     
     
         3 . The method of  claim 1 , wherein the cancer is from a resistant tumor. 
     
     
         4 . The method of  claim 1 , wherein the PI3 kinase inhibitor is selected from -methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, compound 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one BGT, 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A method for treating a Hedgehog-related cancer in a patient in need thereof comprising administering to the patient a Smoothened inhibitor and a Gli inhibitor, wherein the Smoothened inhibitor is 2-methyl-4′-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide or 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-propan-2-ol or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method of  claim 5 , wherein the cancer is a medulloblastoma. 
     
     
         7 . The method of  claim 5 , wherein the cancer is from a resistant tumor. 
     
     
         8 . The method of  claim 5 , wherein the GIi inhibitor is selected from GANT61 and GANT58. 
     
     
         9 . The method of  claim 5 , wherein the GIi inhibitor is selected from zerumbone, zerumbone epoxide, staurosporinone, 6-hydroxystaurosporinone, arcyriaflavin C, and 5,6-dihydroxyarcyriaflavin A, physalin F, and physalin B. 
     
     
         10 . A method for treating a Hedgehog-related cancer in a patient in need thereof comprising administering to the patient a Smoothened inhibitor and a statin, wherein the Smoothened inhibitor is 2-methyl-4′-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide, 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5,4]-propan-2-ol or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of  claim 10 , wherein the cancer is a medulloblastoma. 
     
     
         12 . The method of  claim 10 , wherein the cancer is from a resistant tumor. 
     
     
         13 . The method of  claim 10 , wherein the statin is selected from pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, and pitavastatin.