Agents that inhibit ngly1 and methods of use thereof

Abstract

Methods are provided for treatment of cancer cells, in a regimen comprising contacting the cancer cells with an inhibitor on NGly1, optionally in combination with a direct proteasome inhibitor.

What is claimed is: 
     
         1 . A method of treating cancer, the method comprising:
 contacting cancer cells with a dose of an NGly1 inhibitor effective to reduce expression of a cancer cell proteasome, wherein the number of viable cancer cells is reduced.   
     
     
         2 . The method of  claim 1 , further comprising concomitant administration of an effective dose of a direct proteasome inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the direct prroteasome inhibitor is one or more of bortezomib, carfilzomib, ixazomib, delanzomib, oprozomib, marizomib, IPSI-001, ONX-0914, and PR-924. 
     
     
         4 . The method of  claim 2  or  claim 3 , wherein the combination provides for a synergistic effect relative to the administration of either agent as a single agent. 
     
     
         5 . The method of any of  claims 2 - 4 , wherein the effective dose of direct proteasome inhibitor is lower than the effective dose in the absence of the NGly1 inhibitor. 
     
     
         6 . The method of any of  claims 2 - 5 , wherein the period of time over which the direct proteasome inhibitor is effective is longer than the period of time it is effective in the absence of the NGly1 inhibitor. 
     
     
         7 . The method of any of  claims 1 - 6 , wherein the cancer is a hematologic cancer. 
     
     
         8 . The method of  claim 7 , wherein the hematologic cancer is multiple myeloma. 
     
     
         9 . The method of any of  claims 1 - 8 , wherein the Ngly1 inhibitor does not inhibit caspase activity. 
     
     
         10 . The method of any of  claims 1 - 9 , wherein the NGly1 inhibitor inhibits Ngly1 mechanistically by inhibiting nucleophilic attack of a cysteine residue at the amide linkage between the asparagine side chain of the target protein and the N-linked oligosaccharide. 
     
     
         11 . The method of any of  claims 1 - 10 , wherein the NGly1 inhibitor has a structure of Formula I: 
       
         
           
           
               
               
           
         
         where R 1  is H, alkyl including lower alkyls, branched alkyls, substituted alkyls, aryl, alkaryl, substituted aryl, substituted alkaryl; 
         R 2  is H, alkyl including lower alkyls, branched alkyls, substituted alkyls, aryl, alkaryl, substituted aryl, substituted alkaryl; and 
         R 3  is alkyl including lower alkyls, branched alkyls, substituted alkyls, aryl, alkaryl, substituted aryl, substituted alkaryl, an electron withdrawing substituent, or an electron donating group. 
       
     
     
         12 . The method of  claim 11 , wherein the NGly1 inhibitor has a structure of formula II: 
       
         
           
           
               
               
           
         
         where X is a chloro, bromo, fluoro or iodo substituent. 
       
     
     
         13 . The method of  claim 11 , wherein the NGly1 inhibitor has a structure of Formula 
       
         
           
           
               
               
           
         
         R 4  is an alkyl group, including lower alkyls, e.g. methyl, ethyl, propyl, isopropyl; 
         R 5  is polar or non-polar group, including but not limited to alkynyl, alkenyl, morpholino, amino, amido, sulfhydryl. 
       
     
     
         14 . The method of  claim 11 , wherein the NGly1 inhibitor has a structure of Formula IV: 
       
         
           
           
               
               
           
         
         R 6  is an optional substituent on the aryl ring in any location (ortho, meta, or para), which substitutent may be alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl, —SO 2 -heteroaryl, or fused heterocycle; 
         any of X 1 , X 2  and X 3  are optionally a heteroatom selected from nitrogen, oxygen, sulfur, phosphorus or silicon. 
       
     
     
         15 . The method of any of  claims 1 - 13  wherein the NGly1 inhibitor is: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of any of  claims 1 - 10 , wherein the NGly1 inhibitor is an epoxyketone of Formula V 
       
         
           
           
               
               
           
         
         where R 7  is an amine, substituted amine, amide, substituted amide, alkyl including lower alkyls, branched alkyls, substituted alkyls, aryl, alkaryl, substituted aryl, substituted alkaryl, etc. 
       
     
     
         17 . A composition for use in the methods of any of  claims 1 - 16 , comprising an effective dose of an NGly1 inhibitor; and a pharmaceutically acceptable carrier. 
     
     
         18 . The composition of  claim 17 , further comprising an effective dose of a direct proteasome inhibitor. 
     
     
         19 . A kit for use in the methods of any of  claims 1 - 16 , comprising an effective dose of an NGly1 inhibitor in a pharmaceutically acceptable carrier; and instructions for use. 
     
     
         20 . The kit of  claim 19 , further comprising an effective dose of a direct proteasome inhibitor.