Mitochondria-targeted anti-tumor agents

Abstract

Described are mitochondria-targeted anti-tumor agents, and methods of making and using the same for the treatment of disorders associated with unwanted cell proliferation.

1 . A composition comprising the formula:
   A-B,   wherein A is a molecular chaperone inhibitor and B is a mitochondria-penetrating moiety and A and B are linked, optionally by a linking moiety, or a pharmaceutically acceptable salt thereof, wherein if A is Shepherdin or a fragment thereof, then B is not Antennapedia helix III homeodomain cell-penetrating peptide (ANT) or a fragment thereof.   
     
     
         2 . The composition of  claim 1 , wherein A is a small molecule selected from the group consisting of an Ansamycin class Hsp90 inhibitor; a geldanamycin analogue Hsp90 inhibitor; a purine-scaffold class Hsp90 inhibitor; a resorcinol Hsp90 inhibitor; and a macrolactone-Hsp90 inhibitor. 
     
     
         3 - 5 . (canceled) 
     
     
         6 . The composition of  claim 1 , wherein B is a mitochondria penetrating peptide. 
     
     
         7 . The composition of  claim 6 , wherein B is selected from the group consisting of a mitofusin peptide, a mitochondrial targeting signal peptide, TAT peptide, ANT peptide, VP22 peptide, or Pep-1 peptide. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The composition of  claim 1 , wherein A comprises 17-allylamino-demethoxygeldamycin (17-AAG). 
     
     
         11 - 12 . (canceled) 
     
     
         13 . The composition of  claim 1 , wherein A comprises 17-dimethylaminogeldanamycin. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . The composition of  claim 1 , wherein B is (aryl) 3 P—. 
     
     
         17 . The composition of  claim 1 , wherein B is 
       
         
           
           
               
               
           
         
       
     
     
         18 . The composition of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is H, alkyl, aryl, or arylalkyl; R 3  is H, alkyl; and R 4  is H, alkyl, alkenyl, aryl, arylalkyl, OR d , wherein R d  is H, alkyl, or arylalkyl. 
       
     
     
         19 - 20 . (canceled) 
     
     
         21 . The composition of  claim 10 , wherein B comprises ANT or a mitochondrial-penetrating fragment thereof. 
     
     
         22 . The composition of  claim 1 , comprising a linking moiety between A and B. 
     
     
         23 . The composition of  claim 22 , wherein the linking moiety is selected from the group consisting of a peptide linker and a chemical linker. 
     
     
         24 . The composition of  claim 1 , wherein the linker moiety is divalent and selected from the group consisting of alkylene, alkenylene, alkynylene, cycloalkylene, arylene, heteroarylene, and peptide linker, wherein any two adjacent carbon-carbon bonds of said alkylene, alkenylene, or alkynylene, can be optionally replaced with one or more of O, NH, S, PR e , C(O)NR f , arylene, heterocycloalkylene, or heteroarylene; wherein R e  and R f  are independently selected from alkyl or aryl. 
     
     
         25 . The composition of  claim 1 , wherein the linker moiety is: 
       
         
           
           
               
               
           
         
       
     
     
         26 - 27 . (canceled) 
     
     
         28 . The composition of  claim 1 , wherein A-B is: 
       
         
           
           
               
               
           
         
         wherein, 
         R 1  is H, alkyl, alkenyl, alkynyl, haloalkyl, aryl, arylalkyl, or R a R b R c Si; 
         R 2  is H, alkyl, aryl, or arylalkyl; R 3  is H, alkyl; R 4  is H, alkyl, alkenyl, aryl, arylalkyl, OR d , wherein R d  is H, alkyl, or arylalkyl; 
         R a , R b , and R c  are independently selected from alkyl or aryl; and 
         n is an integer between 1 and 10, inclusive; or a pharmaceutically acceptable salt thereof. 
       
     
     
         29 - 30 . (canceled) 
     
     
         31 . The composition of  claim 1 , wherein A-B is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         32 . (canceled) 
     
     
         33 . The composition of  claim 1 , wherein A-B is: 
       
         
           
           
               
               
           
         
         wherein, q is 1, 2, 3, 4, 5, or 6; and X is a pharmaceutically acceptable counter-ion. 
       
     
     
         34 - 36 . (canceled) 
     
     
         37 . The composition of  claim 1 , wherein A-B is: 
       
         
           
           
               
               
           
         
       
     
     
         38 . A method for inducing cancer or tumor cell death, the method comprising administering to the subject the composition of  claim 1  in an amount sufficient to induce cancer cell death. 
     
     
         39 . A method for inducing cancer or tumor cell death, the method comprising:
 identifying a subject having cancer or a tumor;   determining whether cells of said cancer or tumor have increased mitochondrial concentrations of a chaperone as compared to a control cell;   if the subject has increased mitochondrial levels of the chaperone, administering to the mammal a mitochondrial-targeted chaperone inhibitor comprising the formula:
   A-B, 
   wherein A is a chaperone inhibitor and B is a mitochondria-penetrating moiety and A and B are linked, optionally by a linking moiety.   
     
     
         40 - 41 . (canceled)