Peptidomimetic macrocycles

Abstract

Disclosed are peptidomimetic macrocycles comprising a helix, such as an alpha helix, and methods of using such macrocycles for the treatment of disease such as cancer. In other aspects, the peptidomimetic macrocycle comprises an a,a-disubstituted amino acid, or may comprise a crosslinker linking the a-positions of at least two amino acids or at least one of said two amino acids may be an a,a-disubstituted amino acid. Further included is the targeting of components of the Wnt signaling pathway such as the Tcf4-/3-catenin complex.

What is claimed is: 
     
         1 . A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Table 1. 
     
     
         2 . The peptidomimetic macrocycle of  claim 1 , wherein the amino acid sequence of said peptidomimetic macrocycle is at least about 80% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Table 1. 
     
     
         3 . The peptidomimetic macrocycle of  claim 1 , wherein the amino acid sequence of said peptidomimetic macrocycle is at least about 90% identical to an amino acid sequence chosen from the group consisting of the amino acid sequences in Table 1. 
     
     
         4 . The peptidomimetic macrocycle of  claim 1 , wherein the amino acid sequence of said peptidomimetic macrocycle is chosen from the group consisting of the amino acid sequences in Table 1. 
     
     
         5 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises a helix. 
     
     
         6 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises an α-helix. 
     
     
         7 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid. 
     
     
         8 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises a crosslinker linking the α-positions of at least two amino acids. 
     
     
         9 . The peptidomimetic macrocycle of  claim 8 , wherein at least one of said two amino acids is an α,α-disubstituted amino acid. 
     
     
         10 . The peptidomimetic macrocycle of  claim 8 , wherein the peptidomimetic macrocycle has the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         each A, C, D, and E is independently a natural or non-natural amino acid; 
         B is a natural or non-natural amino acid, amino acid analog, 
       
       
         
           
           
               
               
           
         
       
       [—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
 R 1  and R 2  are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; 
 R 3  is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; 
 L is a macrocycle-forming linker of the formula -L 1 -L 2 -; 
 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 ; 
 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; 
 R 7  is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue; 
 R 8  is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue; 
 v and w are independently integers from 1-1000; 
 u, x, y and z are independently integers from 0-10; and 
 n is an integer from 1-5. 
 
     
     
         11 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises a crosslinker linking a backbone amino group of a first amino acid to a second amino acid within the peptidomimetic macrocycle. 
     
     
         12 . The peptidomimetic macrocycle of  claim 11 , wherein the peptidomimetic macrocycle has the formula (IV) or (IVa): 
       
         
           
           
               
               
           
         
         wherein: 
         each A, C, D, and E is independently a natural or non-natural amino acid; 
         B is a natural or non-natural amino acid, amino acid analog, 
       
       
         
           
           
               
               
           
         
       
       [—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
 R 1  and R 2  are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-, or part of a cyclic structure with an E residue; 
 R 3  is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; 
 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 ; 
 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; 
 R 7  is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; 
 v and w are independently integers from 1-1000; 
 u, x, y and z are independently integers from 0-10; and 
 n is an integer from 1-5. 
 
     
     
         13 . A method of treating cancer in a subject comprising administering to the subject a peptidomimetic macrocycle of  claim 1 . 
     
     
         14 . A method of modulating the activity of β-catenin in a subject comprising administering to the subject a peptidomimetic macrocycle of  claim 1 . 
     
     
         15 . A method of antagonizing the interaction between β-catenin and TCF/LEF proteins in a subject comprising administering to the subject a peptidomimetic macrocycle of  claim 1 . 
     
     
         16 . The peptidomimetic macrocycle of  claim 10 , wherein L 1  and L 2  are independently alkylene, alkenylene or alkynylene. 
     
     
         17 . The peptidomimetic macrocycle of  claim 10 , wherein L 1  and L 2  are independently C 3 -C 10  alkylene or alkenylene 
     
     
         18 . The peptidomimetic macrocycle of  claim 16 , wherein L 1  and L 2  are independently C 3 -C 6  alkylene or alkenylene. 
     
     
         19 . The peptidomimetic macrocycle of  claim 10 , wherein R 1  and R 2  are H. 
     
     
         20 . The peptidomimetic macrocycle of  claim 10 , wherein R 1  and R 2  are independently alkyl. 
     
     
         21 . The peptidomimetic macrocycle of  claim 10 , wherein R 1  and R 2  are methyl.