Peptidomimetic macrocycles

Abstract

The present invention provides novel peptidomimetic macrocycles and methods of using such macrocycles for the treatment of disease.

1 . A peptidomimetic macrocycle comprising an amino acid sequence which is at least 60% identical to the amino acid sequence of: SEQ ID NO. 254, SEQ ID NO. 289, SEQ ID NO. 290, SEQ ID NO. 374, SEQ ID NO. 375, SEQ ID NO. 507, SEQ ID NO. 533, SEQ ID NO. 587, SEQ ID NO. 605, SEQ ID NO. 624, SEQ ID NO. 642, SEQ ID NO. 699, SEQ ID NO. 702, SEQ ID NO. 703, SEQ ID NO. 704, SEQ ID NO. 714, SEQ ID NO. 734, or SEQ ID NO. 
     
     
         2 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 80% identical to the amino acid sequence of: SEQ ID NO. 254, SEQ ID NO. 289, SEQ ID NO. 290, SEQ ID NO. 374, SEQ ID NO. 375, SEQ ID NO. 507, SEQ ID NO. 533, SEQ ID NO. 587, SEQ ID NO. 605, SEQ ID NO. 624, SEQ ID NO. 642, SEQ ID NO. 699, SEQ ID NO. 702, SEQ ID NO. 703, SEQ ID NO. 704, SEQ ID NO. 714, SEQ ID NO. 734, or SEQ ID NO. 742. 
     
     
         3 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 90% identical to the amino acid sequence of: SEQ ID NO. 254, SEQ ID NO. 289, SEQ ID NO. 290, SEQ ID NO. 374, SEQ ID NO. 375, SEQ ID NO. 507, SEQ ID NO. 533, SEQ ID NO. 587, SEQ ID NO. 605, SEQ ID NO. 624, SEQ ID NO. 642, SEQ ID NO. 699, SEQ ID NO. 702, SEQ ID NO. 703, SEQ ID NO. 704, SEQ ID NO. 714, SEQ ID NO. 734, or SEQ ID NO. 742. 
     
     
         4 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least 95% identical to the amino acid sequence of: SEQ ID NO. 254, SEQ ID NO. 289, SEQ ID NO. 290, SEQ ID NO. 374, SEQ ID NO. 375, SEQ ID NO. 507, SEQ ID NO. 533, SEQ ID NO. 587, SEQ ID NO. 605, SEQ ID NO. 624, SEQ ID NO. 642, SEQ ID NO. 699, SEQ ID NO. 702, SEQ ID NO. 703, SEQ ID NO. 704, SEQ ID NO. 714, SEQ ID NO. 734, or SEQ ID NO. 742. 
     
     
         5 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is: SEQ ID NO. 254, SEQ ID NO. 289, SEQ ID NO. 290, SEQ ID NO. 374, SEQ ID NO. 375, SEQ ID NO. 507, SEQ ID NO. 533, SEQ ID NO. 587, SEQ ID NO. 605, SEQ ID NO. 624, SEQ ID NO. 642, SEQ ID NO. 699, SEQ ID NO. 702, SEQ ID NO. 703, SEQ ID NO. 704, SEQ ID NO. 714, SEQ ID NO. 734, or SEQ ID NO. 742. 
     
     
         6 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises a helix. 
     
     
         7 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises an α-helix. 
     
     
         8 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid. 
     
     
         9 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises a crosslinker linking the α-positions of at least two amino acids within the peptidomimetic macrocycle. 
     
     
         10 . The peptidomimetic macrocycle of  claim 9 , wherein at least one of the two amino acids is an α,α-disubstituted amino acid. 
     
     
         11 . The peptidomimetic macrocycle of any one of  claims 1 - 10 , wherein the peptidomimetic macrocycle has the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         each A, C, D, and E is independently a natural or non-natural amino acid, and each D and E independently optionally includes a capping group; 
         each B is independently a natural or non-natural amino acid, amino acid analog, or 
       
       
         
           
           
               
               
           
         
          ; 
         each R 1  and R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; 
         each R 3  is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; 
         each L is independently a macrocycle-forming linker of the formula -L 1 -L 2 -; 
         each L 1  and L 2  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each 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 , 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 optionally substituted with R 5 , or forms 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 optionally substituted with R 5 , or forms part of a cyclic structure with an E residue; 
         each v and w is independently an integer from 1-1000; 
         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. 
       
     
     
         12 . The peptidomimetic macrocycle of  claim 11 , wherein L does not include a thioether or a triazole. 
     
     
         13 . The peptidomimetic macrocycle of  claim 1 , wherein the peptidomimetic macrocycle comprises a cross linker linking a backbone amino group of a first amino acid within the peptidomimetic macrocycle to a second amino acid within the peptidomimetic macrocycle. 
     
     
         14 . The peptidomimetic macrocycle of  claim 13 , 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, and each D and E independently optionally include a capping group; 
         each B is independently a natural or non-natural amino acid, amino acid analog, or 
       
       
         
           
           
               
               
           
         
          ; 
         each R 1  and R 2  is 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; 
         each R 3  is independently hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ; 
         each L 1  and L 2  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R 4 —K—R 4 —] n , each 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 , 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, optionally substituted with R 5 ; 
         each v and w is independently an integer from 1-1000; 
         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. 
       
     
     
         15 . The peptidomimetic macrocycle of  claim 14 , wherein L 1  and L 2  either alone or in combination do not include a thioether or a triazole. 
     
     
         16 . The peptidomimetic macrocycle of  claim 11 , wherein L 1  and L 2  are independently alkylene, alkenylene or alkynylene. 
     
     
         17 . The peptidomimetic macrocycle of  claim 11 , wherein L 1  and L 2  are independently C 3 -C 10  alkylene or C 3 -C 10  alkenylene. 
     
     
         18 . The peptidomimetic macrocycle of  claim 17 , wherein L 1  and L 2  are independently C 3 -C 6  alkylene or C 3 -C 6  alkenylene. 
     
     
         19 . The peptidomimetic macrocycle of  claim 11 , wherein R 1  and R 2  are H. 
     
     
         20 . The peptidomimetic macrocycle of  claim 11 , wherein R 1  and R 2  are independently alkyl. 
     
     
         21 . The peptidomimetic macrocycle of  claim 11 , wherein R 1  and R 2  are methyl. 
     
     
         22 . A method of treating cancer in a subject comprising administering to the subject a peptidomimetic macrocycle of  claims 1 . 
     
     
         23 . A method of modulating the activity of a p53 protein, a HDM2 protein, a HDMX protein, or a combination thereof, in a subject comprising administering to the subject a peptidomimetic macrocycle of  claim 1 . 
     
     
         24 . A method of antagonizing the interaction between a p53 protein and a HDM2 protein, between a p53 protein and a HDMX protein, or a combination thereof, in a subject comprising administering to the subject a peptidomimetic macrocycle of  claim 1 .