ENPP1 Inhibitors and Their Use for the Treatment of Cancer

Abstract

Compounds, compositions and methods are provided for the inhibition of ENPP1. Aspects of the subject methods include contacting a sample with a ENPP1 inhibitor to inhibit cGAMP hydrolysis activity of ENPP1. In some cases, the ENPP1 inhibitor is cell impermeable. Also provided are compositions and methods for treating cancer. Aspects of the methods include administering to a subject a therapeutically effective amount of a ENPP1 inhibitor to treat the subject for cancer. In certain cases, the cancer is a solid tumor cancer. Also provided are methods of administering radiation therapy to a subject either before or after administering an ENPP1 inhibitor. The radiation therapy can be administered at a dosage and/or frequency effective to reduce radiation damage to the subject. In certain cases, the method is performed in combination with a chemotherapeutic agent, or a checkpoint inhibitor, or both.

What is claimed is: 
     
         1 . An ENPP1 inhibitor of the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 X is a hydrophilic head group selected from phosphonic acid, phosphonate, phosphonate ester, phosphate, phosphate ester, thiophosphate, thiophosphate ester, phosphoramidate and thiophosphoramidate; 
 L is a linker; 
 Z 1  and Z 2  are each independently selected from CR 1  and N; 
 Z 3  and Z 4  are each independently selected from CR and N, wherein R is H, alkyl or substituted alkyl; 
 each R 1  is independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocycle and substituted heterocycle; 
 R 2  and R 5  are each independently selected from H, OH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, —OCF 3 , halogen, amine, substituted amine, amide, heterocycle and substituted heterocycle; 
 R 3  and R 4  are each independently selected from H, OH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, —OCF 3 , halogen, amine, substituted amine, amide, heterocycle and substituted heterocycle; or R 3  and R 4  together with the carbon atoms to which they are attached form a fused selected from heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, aryl and substituted aryl; 
 or a pro-drug, a pharmaceutically acceptable salt or a solvate thereof. 
 
     
     
         2 . The ENPP1 inhibitor of  claim 1 , wherein:
 L is selected from —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 — and —(CH 2 ) 6 —;   X is selected from:   
       
         
           
           
               
               
           
         
       
       wherein:
 R a  and R b  are each independently selected from aryl, alkyl, —CH 2 OC(O)R e , —CH 2 OC(O)OR e ; and 
 R c  and R d  are each independently selected from —C(CH 3 )C(O)OR e , alkyl and wherein R e  is alkyl. 
 
     
     
         3 . The ENPP1 inhibitor of  claim 2 , wherein the inhibitor is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 Z 1  and Z 2  are each N; 
 Z 3  is N; and 
 Z 4  is CH or N. 
 
     
     
         4 . The ENPP1 inhibitor of any one of  claims 1 - 3 , wherein the inhibitor comprises a group selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The ENPP1 inhibitor of  claim 1 , wherein the inhibitor is a compound of Table 1 or Table 2. 
     
     
         6 . A method of inhibiting ENPP1, the method comprising:
 contacting a sample comprising ENPP1 with an ENPP1 inhibitor to inhibit cGAMP hydrolysis activity of the ENPP1, wherein the ENPP1 inhibitor is of formula (I):
   Y-A-L-X   (I)
 
   
       wherein:
 Y is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocycle, substituted carbocycle, heterocycle and substituted heterocycle; 
 A is selected from carbocycle, substituted carbocycle, heterocycle and substituted heterocycle; 
 L is a covalent bond or a linker; and 
 X is a hydrophilic head group, 
 or a pro-drug, a pharmaceutically acceptable salt or a solvate thereof. 
 
     
     
         7 . The method of  claim 6 , wherein the ENPP1 inhibitor is cell impermeable. 
     
     
         8 . The method of  claim 6  or  7 , wherein the sample is a cellular sample. 
     
     
         9 . The method of  claim 8 , wherein the sample comprises cGAMP and cGAMP levels are elevated in the cellular sample relative to a control sample not contacted with the inhibitor. 
     
     
         10 . The method of  claim 6 , wherein the hydrophilic head group (X) is selected from phosphonic acid, phosphonate, phosphonate ester, phosphate, phosphate ester, thiophosphate, thiophosphate ester, phosphoramidate and thiophosphoramidate. 
     
     
         11 . The method of  claim 10 , wherein L-X comprises a group of formula (XI): 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 12  is selected from O and S; 
 Z 13  and Z 14  are each independently selected from O and NR′ wherein R′ is H, alkyl or substituted alkyl; 
 Z 15  is selected from O and CH 2 ; 
 R 15  and R 16  are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, aryl, substituted aryl, an acyl group, heterocycle, substituted heterocycle cycloalkyl and substituted cycloalkyl; and 
 q 1  is an integer from 0 to 5. 
 
     
     
         12 . The method of any one of  claims 6 - 11 , wherein A is selected from piperidine, substituted piperidine, piperazine and substituted piperazine. 
     
     
         13 . The method of  claim 12 , wherein A is: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of any one of  claims 6 - 13 , wherein L is —(CH 2 )n-, and n is 1-6. 
     
     
         15 . The method of any one of  claims 6 - 14 , wherein Y is selected from quinazoline, substituted quinazoline, quinoline, substituted quinoline, naphthalene, substituted naphthalene, isoquinoline, substituted isoquinoline, 7H-purine, substituted 7H-purine, pyrimidine, substituted pyrimidine. 
     
     
         16 . The method of  claim 15 , wherein Y is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 1  and Z 2  are each independently selected from CR 1  and N; 
 each R 1  is independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocycle and substituted heterocycle; 
 R 2  and R 5  are each independently selected from H, OH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, —OCF 3 , halogen, amine, substituted amine, amide, heterocycle and substituted heterocycle; 
 R 3  and R 4  are each independently selected from H, OH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, —OCF 3 , halogen, amine, substituted amine, amide, heterocycle and substituted heterocycle; or R 3  and R 4  together with the carbon atoms to which they are attached form a fused ring selected from heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, aryl and substituted aryl. 
 
     
     
         17 . A pharmaceutical composition, comprising:
 a ENPP1 inhibitor of any one of  claims 1 - 5 ; and   a pharmaceutically acceptable excipient.   
     
     
         18 . A method of treating cancer, the method comprising:
 administrating to a subject with cancer a therapeutically effective amount of an ENPP1 inhibitor to treat the subject for cancer,   wherein the ENPP1 inhibitor is of formula (I):
   Y-A-L-X   (I)
 
   wherein:
 Y is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, carbocycle, substituted carbocycle, heterocycle and substituted heterocycle; 
 A is selected from carbocycle, substituted carbocycle, heterocycle and substituted heterocycle; 
 L is a covalent bond or a linker; and 
 X is a hydrophilic head group, 
   or a pro-drug, a pharmaceutically acceptable salt or a solvate thereof.   
     
     
         19 . The method of  claim 18 , where the cancer is a solid tumor cancer. 
     
     
         20 . The method of  claim 18  or  19 , wherein the cancer is breast cancer.