Peptidomimetic macrocycles and uses thereof

Abstract

Methods for treating a solid tumor, determined to lack a p53 deactivation mutation, in a subject are provided. Also provided are peptidomimetic macrocycles for use in treatment of a solid tumor, determined to lack a p53 deactivation mutation, in a subject.

228 - 454 . (canceled) 
     
     
         455 . A pharmaceutical composition comprising a therapeutically effective amount of a peptidomimetic macrocycle or a pharmaceutically-acceptable salt thereof and lenalidomide, wherein the peptidomimetic macrocycle binds to a MDM2 protein. 
     
     
         456 . The pharmaceutical composition of  claim 455 , wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof comprises a capping group. 
     
     
         457 . The pharmaceutical composition of  claim 456 , wherein the capping group comprises a substituted amine. 
     
     
         458 . The pharmaceutical composition of  claim 455 , wherein the peptidomimetic macrocycle has the formula: 
       
         
           
           
               
               
           
         
         wherein:
 each A, C, D and E is independently an amino acid; 
 each B is independently an amino acid, 
 
       
       
         
           
           
               
               
           
         
         
            [—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -]; 
           each R 1  and R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids; 
           each R 3  independently is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; 
           each L and L′ is independently a macrocycle-forming linker of the formula-L 1 -L 2 -; 
           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 independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; 
           each K is independently 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 , or a fluorescent moiety; 
           each R 6  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, or a fluorescent moiety; 
           each R 7  is independently —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; 
           each R 8  is independently —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; 
           each v is independently an integer; 
           each w is independently an integer from 3-1000; 
           u is an integer from 1-10; 
           each x, y and z is independently an integer from 0-10; and 
           each n is independently an integer from 1-5. 
         
       
     
     
         459 . The pharmaceutical composition of  claim 458 , wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof comprises an α-helix. 
     
     
         460 . The pharmaceutical composition of  claim 458 , wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof comprises an α,α-disubstituted amino acid. 
     
     
         461 . The pharmaceutical composition of  claim 458 , wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof comprises an amino acid sequence which is at least about 60% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 10-SEQ ID NO. 692. 
     
     
         462 . The pharmaceutical composition of  claim 455 , wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof comprises an amino acid that is an amino acid analog. 
     
     
         463 . The pharmaceutical composition of  claim 455 , wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof disrupts an interaction between MDM2 and p53. 
     
     
         464 . The pharmaceutical composition of  claim 455 , wherein the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof reactivates p53 upon administration of the pharmaceutical composition to a subject. 
     
     
         465 . The pharmaceutical composition of  claim 458 , wherein:
 the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof comprises a capping group;   the capping group comprises a substituted amine; and   the peptidomimetic macrocycle or pharmaceutically-acceptable salt thereof reactivates p53 upon administration of the pharmaceutical composition to a subject.   
     
     
         466 . A peptidomimetic macrocycle, wherein the peptidomimetic macrocycle has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt thereof, wherein:
 each A, C, D and E is independently an amino acid; 
 each B is independently an amino acid, 
 
       
       
         
           
           
               
               
           
         
         
            [—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -]; 
           each R 1  and R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids; 
           each R 3  independently is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; 
           each L and L′ is independently a macrocycle-forming linker of the formula-L 1 -L 2 -; 
           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 independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; 
           each K is independently 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 , or a fluorescent moiety; 
           each R 6  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, or a fluorescent moiety; 
           each R 7  is independently —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; 
           each R 8  is independently —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; 
           each v is independently an integer; 
           each w is independently an integer from 3-1000; 
           u is an integer from 1-10; 
           each x, y and z is independently an integer from 0-10; and 
           each n is independently an integer from 1-5. 
         
         wherein:
 a terminal D or a terminal E includes a capping group; 
 the capping group comprises a substituted amine; 
 the peptidomimetic macrocycle comprises a therapeutic agent; 
 the therapeutic agent is lenalidomide; and 
 the peptidomimetic macrocycle reactivates p53 upon administration to a subject. 
 
       
     
     
         467 . The peptidomimetic macrocycle of  claim 466 , wherein the terminal E includes a capping group. 
     
     
         468 . The peptidomimetic macrocycle of  claim 466 , wherein the terminal D includes a capping group. 
     
     
         469 . The peptidomimetic macrocycle of  claim 466 , wherein the substituted amine is a primary amine, a secondary amine, or a pegylated secondary amine. 
     
     
         470 . The peptidomimetic macrocycle of  claim 466 , wherein the peptidomimetic macrocycle binds to a MDM2 protein. 
     
     
         471 . The peptidomimetic macrocycle of  claim 466 , wherein the peptidomimetic macrocycle comprises an α-helix. 
     
     
         472 . The peptidomimetic macrocycle of  claim 466 , wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid. 
     
     
         473 . The peptidomimetic macrocycle of  claim 466 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least about 70% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 10-SEQ ID NO. 692. 
     
     
         474 . The peptidomimetic macrocycle of  claim 466 , wherein the peptidomimetic macrocycle comprises an amino acid that is an amino acid analog.