Inhibitors for steroid response elements and rna polymerase ii and related methods

Abstract

The present invention relates to polyamides capable of inhibiting ARE-, GRE- and ERE-mediated gene regulation in cells. The present invention also relates to polyamides capable of modulating the activity of RNA polymerase II and p53. The invention also relates to methods to treat diseases related to ARE-, GRE- and ERE-mediated gene regulation and to RNA polymerase II and p53 activity.

1 . A composition comprising a polyamide of structure 81 as follows: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The composition of  claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         3 . A method of drug administration comprising administering to a subject a polyamide of structure 1 as follows: 
       
         
           
           
               
               
           
         
         wherein each X is independently CH or N; wherein p next to R 3  is 1; wherein R 1  is structure 46 as follows: 
       
       
         
           
           
               
               
           
         
         wherein Y is selected from structures 55 and 57 as follows: 
       
       
         
           
           
               
               
           
         
         wherein t is 1; wherein each R 2  is a C1 alkyl; wherein R 3  is linked to R 4  by structure 4 as follows: 
       
       
         
           
           
               
               
           
         
         wherein R 5  is H and wherein the p next to R 5  is 0; wherein R 7  is H; and wherein R 8  is selected from NH 3   +  and NHAc. 
       
     
     
         4 . The method of  claim 3 , wherein said polyamide has an affinity for DNA sequences found in an ARE, a GRE, or an ERE. 
     
     
         5 . The method of  claim 3 , wherein said polyamide inhibits gene expression mediated by ARE, GRE, or ERE. 
     
     
         6 . The method of  claim 3 , wherein the composition is administered to the subject by parenteral administration. 
     
     
         7 . The method of  claim 3 , wherein the polyamide has structure 81 as follows: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 7 , wherein said subject has breast cancer. 
     
     
         9 . The method of  claim 7 , wherein said method inhibits gene regulation that is mediated by ERE. 
     
     
         10 . The method of  claim 3 , wherein the polyamide has structure 78 as follows: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 10 , wherein said subject has prostate cancer, breast cancer, or ovarian cancer. 
     
     
         12 . The method of  claim 11 , wherein said prostate cancer is therapy resistant prostate cancer. 
     
     
         13 . The method of  claim 10 , wherein said method inhibits gene regulation that is mediated by ARE or GRE. 
     
     
         14 . The method of  claim 3 , wherein the polyamide has structure 82 as follows: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 14 , wherein said subject has breast cancer. 
     
     
         16 . The method of  claim 14 , wherein said method inhibits gene regulation that is mediated by ERE.