Bromodomain inhibitors for androgen receptor-driven cancers

Abstract

Methods for treating certain androgen receptor-positive forms of cancer using inhibitors of the CREB binding protein bromodomain are disclosed. In some methods, the AR-positive forms of cancer may be breast cancer, including triple negative forms, hormone receptor positive forms, and HER2-positive forms. In other methods, the AR-positive forms of cancer may be prostate cancer, including metastatic castration resistant prostate cancer. In some embodiments, methods of treating prostate cancer comprise the step of administering to a patient in need thereof the compound (1R,3R)-3-[(7S)-2-[(R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof.

1 . A method of treating breast cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is H or —OH; 
 each R 2  is independently selected from C 1 -C 6  alkyl, halogen, —CN, and —OR 3 , wherein the alkyl is optionally substituted with one or more halogen; 
 each R 3  is independently C 1 -C 6  alkyl, wherein the alkyl is optionally substituted with one or more halogen; and 
 n is 0, 1, 2, or 3. 
 
     
     
         2 . The method of  claim 1 , wherein the breast cancer is triple negative breast cancer. 
     
     
         3 . The method of  claim 1 , wherein the breast cancer is AR+. 
     
     
         4 . The method of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
       optionally wherein:
 the breast cancer is triple negative breast cancer; and/or 
 the breast cancer is AR+. 
 
     
     
         5 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       optionally wherein:
 the breast cancer is triple negative breast cancer; and/or 
 the breast cancer is AR+. 
 
     
     
         6 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       optionally wherein:
 the breast cancer is triple negative breast cancer; and/or 
 the breast cancer is AR+. 
 
     
     
         7 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       optionally wherein:
 the breast cancer is triple negative breast cancer; and/or 
 the breast cancer is AR+. 
 
     
     
         8 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       optionally wherein:
 the breast cancer is triple negative breast cancer; and/or 
 the breast cancer is AR+. 
 
     
     
         9 . A method of treating prostate cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is H or —OH; 
 each R 2  is independently selected from C 1 -C 6  alkyl, halogen, —CN, and —OR 3 , wherein the alkyl is optionally substituted with one or more halogen; 
 each R 3  is independently C 1 -C 6  alkyl, wherein the alkyl is optionally substituted with one or more halogen; and 
 n is 0, 1, 2, or 3. 
 
     
     
         10 . The method of  claim 9 , wherein the prostate cancer is AR+. 
     
     
         11 . The method of  claim 9 , wherein the prostate cancer is AR-v7+. 
     
     
         12 . The method of  claim 9 , wherein the patient is diagnosed with castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer. 
     
     
         13 . The method of  claim 9 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
       optionally wherein:
 the prostate cancer is AR+; and/or 
 the prostate cancer is AR-v7+. 
 
     
     
         14 . The method of  claim 13 , wherein the patient is diagnosed with disease progression following treatment with enzalutamide. 
     
     
         15 . The method of  claim 13 , wherein the patient is diagnosed with castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer. 
     
     
         16 . A method of treating an Androgen Receptor-expressing cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising (1R,3R)-3-[(7S)-2-[(R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 16 , wherein the Androgen Receptor-expressing cancer is AR+ breast cancer, optionally wherein:
 the AR+ breast cancer is triple negative breast cancer; or   the AR+ breast cancer is Her2− breast cancer; or   the AR+ breast cancer is selected from ER− breast cancer, PR− breast cancer, and ER−/PR− breast cancer.   
     
     
         18 . The method of  claim 16 , wherein the Androgen Receptor-expressing cancer is AR+ prostate cancer, optionally wherein the AR+ prostate cancer is AR-v7+. 
     
     
         19 . The method of  claim 16 , wherein the Androgen Receptor-expressing cancer is castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer. 
     
     
         20 . The method of  claim 19 , wherein the patient is diagnosed with disease progression following treatment with enzalutamide. 
     
     
         21 . A method of treating an Androgen Receptor-expressing cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 21 , wherein the Androgen Receptor-expressing cancer is AR+ breast cancer, optionally wherein the AR+ breast cancer is triple negative breast cancer. 
     
     
         23 . The method of  claim 21 , wherein the Androgen Receptor-expressing cancer is AR+ prostate cancer, optionally wherein the AR+ prostate cancer is AR-v7+.