Use of peptide epoxyketones for metastasis suppression

Abstract

The invention provides a method of repressing metastasis of a cancer compromising the administration of a peptide epoxyketone proteasome inhibitor. Furthermore, the method can be performed in combination with the administration of one or more additional therapeutics.

We claim: 
     
         1 . A method for repressing metastasis of a cancer, comprising administering a therapeutically effective amount of a peptide epoxyketone proteasome inhibitor or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the peptide epoxyketone has a structure of formula (I) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         each Ar is independently an aromatic or hetero aromatic group optionally substituted with 1-4 substituents; 
         L is selected from C═O, C═S, and SO 2 ; 
         X is selected from O, S, NH, and N—C 1-6 alkyl; 
         Y is absent or is selected from C═O and SO 2 ; 
         Z is absent or is C 1-6 alkyl; 
         R 1 , R 2 , and R 3  are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, any of which is optionally substituted; 
         R 4  is N(R 5 )L-Z—R 6 ; 
         R 5  is selected from hydrogen, OH, C 1-6 aralkyl-Y—, and C 1-6 alkyl-Y—; 
         R 6  is selected from hydrogen, OR 7 , C 1-6 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and 
         R 7  and R 8  are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl. 
       
     
     
         3 . The method of  claim 1 , wherein the peptide epoxyketone has a structure of Formula (II) or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein 
         L is selected from C═O, C═S, and SO 2 ; 
         X is O; 
         Z is absent, C 1-6 alkyl, or C 1-6 alkoxy; 
         R 1 , R 2 , and R 3  are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, C 1-6 aralkyl, heteroaryl, heterocyclyl, C 1-6 heterocycloalkyl, C 1-6 heteroaralkyl, carbocyclyl, and C 1-6 carbocyclolalkyl; 
         R 4  is selected from hydrogen, C 1-6 aralkyl, and C 1-6 alkyl; 
         R 5  is heteroaryl; and 
         R 6  and R 7  are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl. 
       
     
     
         4 . The method of  claim 3 , wherein the peptide epoxyketone has the following structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method of  claims 1 - 4 , wherein the cancer is breast, cervical, colorectal, hematologic, kidney, lung, melanoma, neurological, pancreatic or prostate. 
     
     
         6 . The method of  claims 1 - 5 , wherein the peptide epoxyketone is administered orally. 
     
     
         7 . The method of  claim 6 , further comprising administering one or more additional therapeutic agents. 
     
     
         8 . A method of treating an individual who has been identified as being susceptible to metastasized cancer, comprising administering to the individual a prophylactically effective amount of a peptide epoxyketone proteasome inhibitor.