Peptidomimetic macrocycles and use thereof in regulating hif1alpha

Abstract

The present invention provides peptidomimetic macrocycles capable of regulating HIF1α and methods of using such macrocycles for the treatment of diseases.

1 - 132 . (canceled) 
     
     
         133 . A method of modulating Hypoxia-Inducible Factor 1-alpha (HIF1α) activity in a cell, comprising administering to the cell an effective amount of a peptidomimetic macrocycle having Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 each A, C, D, and E is independently an amino acid, 
 B is an amino acid, 
 
       
         
           
           
               
               
           
         
          [—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -], wherein A, B, C, D, and E, taken together with the cross-linked amino acids connected by the macrocycle-forming linker L, form the amino acid sequence of the peptidomimetic macrocycle; 
         each L is independently a macrocycle-forming linker of the formula -L 1 -L 2 - or the formula 
       
       
         
           
           
               
               
           
         
         each R 1  and R 2  are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each of which except for —H is optionally substituted with halo; 
         each R 3  is —H, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, each of which except for —H is optionally substituted with R 5 ; 
         each L 1 , L 2 , and L 3  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 -] n , each being optionally substituted with R 5 ;
 each R 4  is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; 
 each K is O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ; 
 
         each R 5  is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR 6 , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope, or a therapeutic agent;
 each R 6  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope, or a therapeutic agent; 
 
         each R 7  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each of which except for —H is optionally substituted with R 5 , or part of a cyclic structure with a D residue; 
         each R 8  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each of which except for —H is optionally substituted with R 5 , or part of a cyclic structure with an E residue; 
         each R 9  is independently alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with R a  and/or R b ; 
         R a  and R b  are independently alkyl, OCH 3 , CF 3 , NH 2 , CH 2 NH 2 , F, Br, I, 
       
       
         
           
           
               
               
           
         
         each v and w is independently integers from 1-100; 
         u is an integer from 1 to 3; 
         each x, y and z is independently integers from 0-10; and 
         each n is independently an integer from 1-5, 
       
       wherein administering of the peptidomimetic macrocycle modulates HIF-1α activity in the cell. 
     
     
         134 . The method of  claim 133 , wherein u is 1. 
     
     
         135 . The method of  claim 133 , wherein the sum of x+y+z is 2, 3, or 6. 
     
     
         136 . The method of  claim 133 , wherein the sum of x+y+z is 3. 
     
     
         137 . The method of  claim 133 , wherein [A]x-[B]y-[C]z comprises Leu-Val-Ile. 
     
     
         138 . The method of  claim 133 , wherein R 1  and R 2  are H. 
     
     
         139 . The method of  claim 133 , wherein R 1  and R 2  are independently alkyl. 
     
     
         140 . The method of  claim 133 , wherein R 1  and R 2  are methyl. 
     
     
         141 . The method of  claim 133 , wherein L 1  and L 2  are independently alkylene, alkenylene, or alkynylene. 
     
     
         142 . The method of  claim 133 , wherein the peptidomimetic macrocycle is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         143 . The method of  claim 133 , wherein the peptidomimetic macrocycle is 
       
         
           
           
               
               
           
         
       
       wherein:
 L′ is a macrocycle-forming linker of the formula -L 1 ′-L 2 ′- or the formula 
 
       
         
           
           
               
               
           
         
         L 1 ′ and L 2 ′ are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 -] n , each being optionally substituted with R 5 ; 
         R 8 ′ is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, each of which except for —H is optionally substituted with R 5 , or part of a cyclic structure with an E residue; 
         R 9 ′ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, or heterocyclyl group, unsubstituted or optionally substituted with R a ′ and/or R b ′; 
         R a ′ and R b ′ are independently alkyl, OCH 3 , CF 3 , NH 2 , CH 2 NH 2 , F, Br, I, 
       
       
         
           
           
               
               
           
         
         and x′, y′, and z′ are independently integers from 0-10. 
       
     
     
         144 . The method of  claim 143 , wherein the sum of x+y+z and the sum of x′+y′+z′ are independently 2, 3, or 6. 
     
     
         145 . The method of  claim 143 , wherein the sum of x+y+z is 3, and the sum of x′+y′+z′ is 3. 
     
     
         146 . The method of  claim 143 , wherein the peptidomimetic macrocycle is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         147 . The method of  claim 133 , wherein the peptidomimetic macrocycle is at least about 70%, 75%, 80%, 85%, 90%, or 95% identical to an amino acid sequence of FIDEEVLMSLVIEMALDRI. 
     
     
         148 . The method of  claim 133 , wherein administering of the peptidomimetic macrocycle inhibits HIF-1α activity in the cell. 
     
     
         149 . The method of  claim 133 , wherein administering of the peptidomimetic macrocycle antagonizes an interaction of HIF1α with CREB-binding protein and/or p300 in the cell. 
     
     
         150 . The method of  claim 133 , wherein administering of the peptidomimetic macrocycle reduces transcription of a gene that is mediated by interaction of HIF1α with CREB-binding protein and/or p300 in the cell. 
     
     
         151 . The method of  claim 133 , wherein administering of the peptidomimetic macrocycle reduces angiogenesis in the cell. 
     
     
         152 . The method of  claim 133 , wherein administering of the peptidomimetic macrocycle induces apoptosis in the cell.