Methods and compositions of trail-death receptor agonists/activators

Abstract

This invention describes a series of methods and compositions for prevention and treatment of diseases such as cancer. One aspect of the invention describes small molecule-based drugs that can be used to bind to death receptors TRAIL-R1/DR4 and/or TRAIL-R2/DR5 and induce apoptosis in cancer cells, while sparing normal cells. The invention also describes TRAIL Death Receptor Agonists/Activators (DRAs) and their uses, such as the induction of apoptosis through caspase-8 and caspase-3 activation. The present invention also describes the methods of treating cancers, such as breast, prostate, colon, pancreatic, ovarian, lung, and brain cancers, leukemia, lymphoma, multiple myeloma, and mesothelioma, using DRAs either as single-agent treatments, or in combination with other therapies.

1 . A method of treating cancer in an individual comprising administering to the individual a therapeutically effective amount of a compound having either the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 1′ , R 2′ , and R 3′ , are each independently —H, hydroxy, amino, cyano, halo, nitro, mercapto, —OPO(OH) 2 , —PO(OH) 2 , —OSO 2 OH, —SO 2 OH, or a heteroatom-substituted or heteroatom-unsubstituted C 1 -C 3 -alkyl, C 2 -C 3 -alkenyl, C 2 -C 3 -alkynyl, C 1 -C 3 -acyl, C 1 -C 3 -alkoxy, C 1 -C 3 -acyloxy, C 1 -C 3 -alkylamino, or C 1 -C 3 -amido; 
 R 4′ , is —H or a heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl, C 1 -C 10 -aryl, C 2 -C 10 -aralkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, or C 1 -C 10 -acyl; 
 X is selected from the group consisting of —O—, —S—, and —NH—, and 
 Y is selected from the groups consisting of hydroxy, amino, and mercapto; 
 
       
       or the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R 1″ , R 2″ , R 3″ , R 4″ , R 5″ , R 6″ , and R 7″ , are each independently —H, hydroxy, amino, cyano, halo, nitro, mercapto, —OPO(OH) 2 , —PO(OH) 2 , —OSO 2 OH, —SO 2 OH, or a heteroatom-substituted or heteroatom-unsubstituted C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 1 -C 8 -aryl, C 2 -C 8 -aralkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -aryloxy, C 2 -C 8 -aralkoxy, C 1 -C 8 -acyloxy, C 1 -C 8 -alkylamino, C 1 -C 8 -arylamino, C 2 -C 8 -aralkylamino, or C 1 -C 8 -amido; 
 Y is selected from the groups consisting of heteroatom-substituted or heteroatom-unsubstituted C 1 -C 15 -alkylamino, C 1 -C 15 -alkenylamino, C 1 -C 15 -alkynylamino, C 1 -C 5 -arylamino, C 2 -C 15 -aralkylamino, and C 1 -C 15 -amido; or 
 
       
       or a pharmaceutically acceptable salt, hydrate, amine-N-oxide, imine-N-oxide, tautomer, or optical isomer of either of the above formulas. 
     
     
         2 - 24 . (canceled) 
     
     
         25 . A method of treating cancer in an individual comprising administering to said individual a therapeutically effective amount of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         26 . A method of inducing apoptosis in a cancer cell comprising:
 (a) obtaining a cancer cell; and   (b) contacting the cancer cell with an effective amount of with a TRAIL-R1/DR4 and/or TRAIL-R2/DR5 agonist, wherein the TRAIL-R1/DR4 and/or TRAIL-R2/DR5 agonist of the formula:   
       
         
           
           
               
               
           
         
         
           wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 1′ ., R 2′ , and R 3′  are each independently —H, hydroxy, amino, cyano, halo, nitro, mercapto, —OPO(OH) 2 , —PO(OH) 2 , —OSO 2 OH, —SO 2 OH, or a heteroatom-substituted or heteroatom-unsubstituted C 1 -C 3 -alkyl, C 2 -C 3 -alkenyl, C 2 -C 3 -alkynyl, C 1 -C 3 -acyl, C 1 -C 3 -alkoxy, C 1 -C 3 -acyloxy, C 1 -C 3 -alkylamino, or C 1 -C 3 -amido; 
 R 4′ , is —H or a heteroatom-substituted or heteroatom-unsubstituted C 1 -C 10 -alkyl, C 1 -C 10 -aryl, C 2 -C 10 -aralkyl, C 2 -C 10 -alkenyl, C 2 -C 10 -alkynyl, or C 1 -C 10 -acyl; 
 X is selected from the group consisting of —O—, —S—, and —NH—, and 
 Y is selected from the groups consisting of hydroxy, amino, and mercapto; 
 
           or a pharmaceutically acceptable salt or tautomer of the formula.