Screening method and compounds for modulating telomerase activity

Abstract

The present invention embraces methods for identifying compounds that modulate the activity of telomerase. Compounds of the invention are identified by designing or screening for a compound which binds to at least one amino acid residue of the TRBD, “thumb,” “finger,” and/or “palm” domain; or FP-pocket, PT-pocket or Th-pocket of telomerase and testing the compound for its ability to modulate the activity of telomerase. Compounds selected for interacting with the T-pocket or Fingers-Palm pocket of telomerase are also provided.

What is claimed is: 
     
         1 . A compound having a structure comprising: 
       
         
           
           
               
               
           
         
       
       wherein
 R 6  is an unsubstituted benzene or heterocyclic group or benzene or heterocyclic group substituted with at least one substituent comprising a lower alkyl, amine, nitro, oxo, hydroxyl, —C(O)CH 3 , or halo group; and 
 R 7  is —NO 2  or —C(O)NH—R 8 , wherein R 8  is an unsubstituted benzene or heterocyclic group or benzene or heterocyclic group substituted with at least one substituent comprising a lower alkyl, amine, nitro, oxo, hydroxyl, —C(O)CH 3 , or halo group. 
 
     
     
         2 . A compound of  claim 1 , selected from the group of compounds listed in Table 11. 
     
     
         3 . A pharmaceutical composition comprising the compound of  claim 1  in admixture with a pharmaceutically acceptable carrier. 
     
     
         4 . The pharmaceutical composition of  claim 3 , further comprising a cancer therapeutic agent. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the cancer therapeutic agent comprises a chemotherapeutic agent or radiotherapeutic agent. 
     
     
         6 . A method for inhibiting telomerase activity comprising contacting telomerase with a compound having the structure of Formula I, II, III or IV: 
       
         
           
           
               
               
           
         
       
       thereby inhibiting the activity of telomerase. 
     
     
         7 . A method for preventing or treating a disease or disorder associated with telomerase comprising administering to a subject in need of treatment a pharmaceutical composition comprising a compound having the structure of Formula I, II, III or IV: 
       
         
           
           
               
               
           
         
       
       thereby preventing or treating the subject's disease or disorder. 
     
     
         8 . The method of  claim 7 , wherein the disease or disorder is cancer. 
     
     
         9 . The method of  claim 8 , wherein the cancer comprises an adenocarcinoma of the breast, prostate, and colon;
 melanoma; non-small cell lung; glioma; leukemia; or cancer of the bone, breast, digestive system, colorectal, liver, pancreatic, pituitary, testicular, orbital, head and neck, central nervous system, acoustic, pelvic, respiratory tract, or urogenital tract.   
     
     
         10 . The method of  claim 8 , wherein the pharmaceutical composition further comprises a cancer therapeutic agent. 
     
     
         11 . The method of  claim 10 , wherein the cancer therapeutic agent comprises a chemotherapeutic agent or radiotherapeutic agent. 
     
     
         12 . The method of  claim 7 , wherein the disease or disorder comprises Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, osteoporosis, diabetes or age-related macular degeneration.