Compositions and methods for treating cancers

Abstract

The invention describes compounds that inhibit both HDAC and GSK3β (i.e., HDAC/GSK3β dual inhibitors). The invention further describes compositions containing these HDAC/GSK3β dual inhibitors, as well as methods and kits using these HDAC/GSK3β dual inhibitors to treat various medical conditions. The invention also provides methods and kits using a HDAC inhibitor and a GSK3β to treat various medical conditions, and compositions containing a HDAC inhibitor and a GSK3β. Medical conditions treatable with various embodiments of the invention include but are not limited to cancers and tumors.

1 .- 107 . (canceled) 
     
     
         108 . A method of treating a cancer in a human subject, comprising:
 administering a therapeutically effective amount of a compound of Formula (IV):   
       
         
           
           
               
               
           
         
         
           wherein: 
           L 1  and L 2  are independently a linker; 
           R 1  is an aromatic moiety, alkyl, acyl, cyclyl or heterocyclyl, each of which can be optionally substituted; 
           R 2  is hydrogen, lower alkyl, cyclyl, heterocyclyl, aryl, or heteroaryl, each of which can be optionally substituted; 
           R 3  is absent or an aromatic moiety, which can be optionally substituted; 
           p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and 
           wherein -L 1 R 1  is linked to one nitrogen of the thiadiazolidine ring and —(CH 2 ) p —R 3 -L 2 -C(O)NHOR 2  is linked to the other nitrogen of the thiadiazolidine ring. 
         
       
     
     
         109 . The method of  claim 108 , wherein the compound has the structure of Formula (VI): 
       
         
           
           
               
               
           
         
       
     
     
         110 . The method of  claim 109 , wherein the compound has the structure of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         X is a linker group; and 
         Y is absent or an aromatic substituent. 
       
     
     
         111 . The method of claim  3 , wherein the compound has the structure of Formula (I-1): 
       
         
           
           
               
               
           
         
         wherein n is an integer from 1 to 12. 
       
     
     
         112 . The method of  claim 108 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         113 . The method of claim  2 , wherein the compound has the structure of Formula (VI): 
       
         
           
           
               
               
           
         
       
     
     
         114 . The method of claim  6 , wherein the compound has the structure of Formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         X is a linker group, and R is -L 1 R 1 . 
       
     
     
         115 . The method of claim  7 , wherein the compound has the structure of Formula (II-1): 
       
         
           
           
               
               
           
         
       
     
     
         116 . The method of  claim 108 , wherein administering the therapeutically effective amount of the compound of Formula (IV) comprises administering a composition comprising the compound linked to a particle. 
     
     
         117 . The method of  claim 116 , wherein the particle is a magnetic particle. 
     
     
         118 . The method of  claim 116 , wherein the compound is linked to the particle via a linker comprising a cleavable linking group. 
     
     
         119 . The method of  claim 118 , wherein the cleavable linking group is cleavable by an enzyme. 
     
     
         120 . The method of  claim 119 , wherein the cleavable linking group is cleavable by an enzyme enriched in a cancer or tumor. 
     
     
         121 . The method of  claim 119 , wherein the cleavable linking group is cleavable by a peptidase enriched in a cancer or tumor. 
     
     
         122 . The method of  claim 119 , wherein the cleavable linking group is a cleavable substrate of Cathepsin G. 
     
     
         123 . The method of  claim 116 , wherein the composition further comprises a pharmaceutically acceptable carrier or excipient. 
     
     
         124 . The method of  claim 116 , wherein the composition is formulated for topical, intravascular, intravenous, intraarterial, intratumoral, intramuscular, subcutaneous, intraperitoneal, intranasal or oral administration. 
     
     
         125 . The method of  claim 116 , further comprising administering an anti-cancer therapeutic agent. 
     
     
         126 . The composition of  claim 125 , wherein the anti-cancer therapeutic agent is a chemotherapeutic agent. 
     
     
         127 . The method of  claim 108 , wherein the cancer is pancreatic cancer.