Pharmaceutical compositions for the treatment of conditions responsive to proteasome inhibition

Abstract

The invention disclosed herein generally relates to methods and compositions for inhibiting proteasome activity comprising a syrbactin compound having the structure of Formula I or II:

1 . A method for inhibiting proteasome activity in a cell comprising:
 contacting a cell with an amount of a compound of the formula:   
       
         
           
           
               
               
           
         
         
           effective to inhibit proteasome activity of said cell; and 
           confirming inhibition of proteasome activity. 
         
       
     
     
         2 . The method of  claim 1 , wherein confirming inhibition of proteasome activity comprises detecting inhibition at least one type of proteasomal activity selected from chymotrypsin-like activity, trypsin-like activity and caspase-like activity; detecting the accumulation of ubiquitinated proteins; performing co-crystallization assays; observing a reduction in tumor size, mass, volume, diameter; surgical biopsy; amelioration of symptoms associated with a condition differentially affected by proteasome inhibition; and the like. 
     
     
         3 . The method of  claim 1 , wherein the compound inhibits a chymotrypsin-like activity of a proteasome of the cell. 
     
     
         4 . The method of  claim 3 , wherein the double bond at the 3,4 position covalently attaches the compound to the threonine residue of a chymotrypsin-like catalytic site of a proteasome of the cell. 
     
     
         5 . The method of  claim 2 , wherein the compound further inhibits a trypsin-like activity of a proteasome of the cell. 
     
     
         6 . The method of  claim 3 , wherein the compound further inhibits a caspase-like activity of a proteasome of the cell. 
     
     
         7 . The method of  claim 1 , wherein the compound is syringolin, or an analog or derivative thereof. 
     
     
         8 . The method of  claim 7 , wherein the compound is syringolin A, or an analog or derivative thereof. 
     
     
         9 . The method of  claim 1 , wherein the compound is glidobactin, or an analog or derivative thereof. 
     
     
         10 . The method of  claim 9 , wherein the compound is glidobactin A. 
     
     
         11 . The method of  claim 1 , wherein the compound is a synthetic derivative or analog of syringolin or glidobactin. 
     
     
         12 . A method for inducing apoptosis of tumor cells, comprising:
 administering to a tumor cell a compound of the formula:   
       
         
           
           
               
               
           
         
          and
 confirming induction of apoptosis. 
 
       
     
     
         13 . The method of  claim 12 , wherein confirming induction of apoptosis comprises detecting p53 levels; detecting cleavage of poly (ADP-ribose) polymerase (PARP); assaying for extraversion of phosphatidyl serine; observing a reduction in tumor size, mass, volume, diameter; surgical biopsy; amelioration of symptoms associated with a condition differentially affected by proteasome inhibition; and the like. 
     
     
         14 . The method of  claim 12 , wherein the compound is syringolin, or an analog or derivative thereof. 
     
     
         15 . The method of  claim 14 , wherein the compound is syringolin A, or an analog or derivative thereof. 
     
     
         16 . The method of  claim 12 , wherein the compound is glidobactin, or an analog or derivative thereof. 
     
     
         17 . The method of  claim 16 , wherein the compound is glidobactin A. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . A method for treating cancer in a subject having cancerous cells, comprising:
 identifying subject having cancerous cells;   administering to the subject a composition comprising:
 (i) an analog of the following compound 
   
       
         
           
           
               
               
           
         
         
            comprising the 12-membered ring structure having a double bond at the 3,4 position, or 
           (ii) an analog of the following compound 
         
       
       
         
           
           
               
               
           
         
         
            comprising the 12-membered ring structure having a double bond at the 3,4 position, 
         
         wherein the administration of (i) or (ii) inhibits the activity of a β5 catalytic subunit of the proteasome of said cancerous cells by covalent attachment of (i) or (ii) to the threonine residue of the β5 subunit of the catalytic site of the proteasome of said cancerous cells, and wherein inhibition of the activity of a β5 catalytic subunit of the proteasome induces cancerous cell growth arrest, reduction in the number of cancerous cells, apoptosis of the cancerous cells, or death of the cancerous cells, thereby treating said subject.