Wortmannin Analogs and Methods of Using Same in Combination with Chemotherapeutic Agents

Abstract

Novel wortmannin analogs and their use in inhibiting PI-3-kinase activity in mammals and the treatment or prevention of cancer and tumor formation in a subject are described herein. Preferably, the wortmannin analogs may be administered with other chemotherapeutic agents in the treatment of cancer.

1 . A method of treating cancer comprising administering to a subject a pharmaceutically effective amount of a compound comprising 
       
         
           
           
               
               
           
         
       
       wherein Y is a heteroatom and R1 or R2 is an unsaturated alkyl, non-linear alkyl, or substituted alkyl respectively, and a chemotherapeutic agent. 
     
     
         2 . The method of  claim 1 , wherein said R1 or R2 is a disubstituted alkyl. 
     
     
         3 . The method of  claim 1 , wherein said chemotherapeutic agent is selected from the group consisting of a cytotoxic agent and a anti-tumor targeting agent. 
     
     
         4 . The method of  claim 2 , wherein said cytotoxic agent is selected from the group consisting of gemcitabine, paclitaxel, and cisplatin. 
     
     
         5 . The method of  claim 2 , wherein said anti-tumor targeting agent is selected from the group consisting of gefitinib, erlotinib, trastuzumab, cetuximab and bevacizumab. 
     
     
         6 . The method of  claim 1 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 1 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein said compound is administered orally. 
     
     
         9 . The method of  claim 1 , wherein said compound is administered intravenously. 
     
     
         10 . The method of  claim 1 , wherein said compound is PX-866 and said chemotherapeutic agent is gefitinib. 
     
     
         11 . The method of  claim 1 , wherein said compound is PX-866 and said chemotherapeutic agent is bevacizumab. 
     
     
         12 . The method of  claim 1 , wherein said compound is PX-867 and said chemotherapeutic agent is gefitinib. 
     
     
         13 . The method of  claim 1 , wherein said compound is PX-867 and said chemotherapeutic agent is bevacizumab. 
     
     
         14 . The method of  claim 1 , further comprising administering an antihyperglycemic agent. 
     
     
         15 . A composition comprising a compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein Y is a heteroatom and R1 or R2 is an unsaturated alkyl, non-linear alkyl, or substituted alkyl respectively, and a chemotherapeutic agent.