Methods and compositions for derepression of IAP-inhibited caspase

Abstract

The invention provides isolated agents having novel chemical structures and possessing superior activity as derepressors of IAP inhibited caspase. The invention further provides a method of derepressing an IAP-inhibited caspase. The invention further provides assay methods employing labeled compounds of the invention, especially fluorescent labeled compounds.

1 . An isolated agent comprising one of the compounds identified herein as TPI 1577-1, TPI 1577-2, TPI 1577-3, TPI 1567-5, TPI 1577-6, TPI 1577-7, TPI 1577-8, TPI 1567-11, TPI 1567-12, TPI 1567-13, TPI 1567-14, TPI 1577-9, TPI 1567-23, TPI 1567-24, TPI 1567-18, TPI 1572-8, TPI 1572-15, TPI 1572-16, TPI 1572-10, TPI 1572-11, TPI 1572-14, TPI 1572-17, TPI 1572-18, TPI 1572-19, TPI 1572-20, TPI 1572-21, TPI 1572-22 or TPI 1572-23.  
     
     
         2 . A composition comprising an isolated agent of  claim 1  in admixture with a diluent.  
     
     
         3 . A pharmaceutical composition comprising the agent of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         4 . A complex comprising an IAP bound to an agent selected from the group consisting of a one of the compounds set forth in  claim 1 .  
     
     
         5 . The complex of  claim 4 , wherein said IAP is selected from the group consisting of XIAP, c-IAP-1, c-IAP-2, NIAP, BRUCE (Appollon), ML-IAP, ILP2, DIAP-1, DIAP-2 and survivin.  
     
     
         6 . A method of derepressing an IAP-inhibited caspase, comprising contacting an IAP-inhibited caspase with an effective amount of an agent to derepress an IAP-inhibited caspase, said agent being selected from the group of agents set forth in  claim 1 .  
     
     
         7 . The method of  claim 6 , wherein said IAP is selected from the group consisting of XIAP, c-IAP-1, c-IAP-2, NIAP, BRUCE (Appollon), ML-IAP, ILP2, DIAP-1, DIAP-2 and survivin.  
     
     
         8 . The method of  claim 6 , wherein said caspase is selected from the group consisting of caspase-3, caspase-7 and caspase-9 and the  drosophila  caspases DCP-1, DRICE and DRONC.  
     
     
         9 . The method of  claim 6 , wherein said contacting is performed in vitro.  
     
     
         10 . The method of  claim 6 , wherein said contacting occurs in a cell.  
     
     
         11 . A method of promoting apoptosis in a cell, comprising contacting a cell with an effective amount of an agent to derepress an IAP-inhibited caspase, said agent having being selected from the group of agents set forth in  claim 1 .  
     
     
         12 . The method of  claim 11 , wherein said cell is a eukaryotic cell.  
     
     
         13 . The method of  claim 11 , wherein said IAP is selected from the group consisting of XIAP, c-IAP-1, c-IAP-2, NIAP, BRUCE (Appollon), ML-IAP, ILP2, DIAP-1, DIAP-2 and survivin.  
     
     
         14 . The method of  claim 11 , wherein said caspase is selected from the group consisting of caspase-3, caspase-7 and caspase-9 and the  drosophila  caspases DCP-1, DRICE and DRONC.  
     
     
         15 . A method of reducing the severity of a pathologic condition in an individual, comprising administering to an individual having a pathologic condition characterized by a pathologically reduced level of apoptosis, an effective amount of an agent to derepress an IAP-inhibited caspase, said agent being selected from the group of agents set forth in  claim 1 .  
     
     
         16 . The method of  claim 15 , wherein said pathologic condition is cancer.  
     
     
         17 . The method of  claim 15 , wherein said pathologic condition is selected from the group consisting of psoriasis, hyperplasia, an autoimmune disease and restenosis.  
     
     
         18 . The method of  claim 15 , wherein said IAP is selected from the group consisting of XIAP, c-IAP-1, c-IAP-2, NIAP, BRUCE (Appollon), ML-IAP, ILP2, DIAP-1, DIAP-2 and survivin.  
     
     
         19 . The method of  claim 15 , wherein said caspase is selected from the group consisting of caspase-3, caspase-7 and caspase-9 and the  drosophila  caspases DCP-1, DRICE and DRONC.  
     
     
         20 . The method of  claim 15 , further comprising administering a second therapeutic agent.  
     
     
         21 - 64 . (canceled)