Methods and Compositions for Re-activating Epstein-Barr Virus and Screening Compounds Therefor

Abstract

In an effort to discover therapies for treating diseases caused by EBV, a novel screening assay for identifying compounds that reactivate EBV latent infection and a family of small molecules based on a tetrahydrocarboline backbone were discovered. Specifically, the compounds have the structure of the formula (I), wherein R 1 -R 11 are defined herein and activate/reactivate EBV in a variety of cell types in a patient and are, therefore, useful in preventing or treating EBV-positive cancer, optionally with an anti-viral agent. In screening these compounds, novel compositions, EBV-positive cell lines, and methods are provided.

What is claimed is: 
     
         1 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         2 . A method for activating Epstein-Barr virus (EBV), said method comprising administering a compound of formula (I) to a subject in need thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is H, C 1  to C 6  alkyl, C 1  to C 6  alkoxy, or halogen; 
 R 2  is H, C 1  to C 6  alkyl, or C 1  to C 6  alkoxy; 
 R 3  is optionally substituted aryl or heteroaryl; 
 R 4  is H or optionally substituted C 1  to C 6  alkyl; 
 R 5  to R 11  are, independently, selected from the group consisting of H and C 1  to C 6  alkyl; 
 R 12  is H, C(O)OR 3 , C(O)NR 3 R 4 , or SO 2 R 3 ; and 
 R 13  is H, optionally substituted aryl, or optionally substituted heteroaryl; 
 
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         3 . The method according to  claim 2 , where the EBV infection is latent in malignant tumor cells. 
     
     
         4 . The method according to  claim 3 , wherein said malignant tumor cells are from lymphoid or epithelial malignancies. 
     
     
         5 . The method according to  claim 3 , wherein said malignancy comprises Burkitt's lymphoma, nasopharyngeal carcinoma, gastric carcinoma, non-Hodgkin lymphoma, or primary CNS lymphoma. 
     
     
         6 . The method according to  claim 2 , further comprising administering a histone deacetylase inhibitor or a proteasome inhibitor. 
     
     
         7 . The method according to  claim 2 , wherein said compound has low toxicity to EBV-negative cells. 
     
     
         8 . The method according to  claim 2 , wherein said compound is selective to EBV-positive cells. 
     
     
         9 . The method according to  claim 2 , further comprising administering an anti-viral agent, a chemotherapeutic, or radiation to said subject. 
     
     
         10 . The method according to  claim 9 , wherein said anti-viral agent, chemotherapeutic, or radiation is administered prior to, concurrently with, or subsequent to administration of said compound. 
     
     
         11 . The method according to  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The method according to  claim 2 , wherein said subject is at risk for developing post-transplant lymphoproliferative disease and is an immunosuppressed subject. 
     
     
         13 . The method according to  claim 2 , wherein said subject has an EBV-positive cancer and said method is useful for treating or suppressing the proliferation of said cancer. 
     
     
         14 . A kit comprising:
 an anti-viral agent; and   a compound of formula (I):   
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is H, C 1  to C 6  alkyl, C 1  to C 6  alkoxy, or halogen; 
 R 2  is H, C 1  to C 6  alkyl, or C 1  to C 6  alkoxy; 
 R 3  is optionally substituted aryl or heteroaryl; 
 R 4  is H or optionally substituted C 1  to C 6  alkyl; 
 R 5  to R 11  are, independently, selected from the group consisting of H and C 1  to C 6  alkyl; 
 R 12  is H, C(O)OR 3 , C(O)NR 3 R 4 , or SO 2 R 3 ; and 
 R 13  is H, optionally substituted aryl, or optionally substituted heteroaryl; 
 
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         15 . The kit according to  claim 14 , further comprising administering a histone deacetylase inhibitor or a proteasome inhibitor. 
     
     
         16 . The kit according to  claim 14 , further comprising an anti-viral agent, a chemotherapeutic, or a radioactive compound.