Selective mcl-1 binding peptides

Abstract

Provided herein are peptides that bind Mcl-1. Also provided are compositions containing these polypeptides and methods of using such peptides in the treatment of cancer that include administering to a subject one of the polypeptides.

1 . A compound comprising the amino acid sequence:
 1F 1G 2A 2B 2C 2D 2E 2F 2G 3A 3B 3C 3D 3E 3F 3G 4A 4B 4C 4D 4E 4F 4G 5A (SEQ ID NO: 1),   wherein 1F is R or a conservative substitution or is missing; 1G is P or a conservative substitution or is missing; 2A is E or a conservative substitution or is missing; 2B is I or a conservative substitution; 2C is W or a conservative substitution; 2D is M or a conservative substitution, or norleucine (B); 2E is T or a conservative substitution, V or a conservative substitution, 2-aminoisobutyric acid (Aib); 2F is Q or a conservative substitution; 2G is G or a conservative substitution; 3A is L or a conservative substitution, F or a conservative substitution, pentafluoro phenylalanine, cyclohexyl alanine (Cha), or homo-cyclohexyl alanine (H-Cha); 3B is R or a conservative substitution, W or a conservative substitution, Q or a conservative substitution, D or a conservative substitution, Y or a conservative substitution, Aib, D-phenyl glycine, α,αmethyl leucine, α,αmethyl phenylalanine; 3C is R or a conservative substitution; 3D is L or a conservative substitution; 3E is G or a conservative substitution; 3F is D or a conservative substitution; 3G is E or a conservative substitution; 4A is I or a conservative substitution; 4B is N or a conservative substitution; 4C is A or a conservative substitution; 4D is Y or a conservative substitution; 4E is Y or a conservative substitution; 4F is A or a conservative substitution; 4G is R or a conservative substitution or is missing; 5A is R or a conservative or is missing;   provided that 2E, 3A, 3B, 4B and 4F are not T, L, R, N and A respectively, and wherein optionally, the side chains of two amino acids separated by 3 or 6 amino acids are replaced by an intermolecular crosslink.   
     
     
         2 . The compound of  claim 1 , wherein 1F, 1G and 2A are missing. 
     
     
         3 . The compound of  claim 1 , wherein 2D, 4B and 4F are B, N and A respectively. 
     
     
         4 . The compound of  claim 3 , comprising at least one amino acid that is not one of the 20 common, naturally-occurring amino acids at a position selected from the group consisting of 2E, 3A, and 3B, wherein every position not in that group is a common, naturally-occurring amino acid. 
     
     
         5 . The compound of  claim 1 , comprising an amino acid sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 8) 
                 
                     
                   IWBTQGChaRRLGDEINAYYARR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 9) 
                 
                     
                     IWBTQGH-ChaRRLGDEINAYYARR , 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 10) 
                 
                     
                     IWBAibQGLRRLGDEINAYYARR . 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 11) 
                 
                     
                     IWBAibQGChaRRLGDEINAYYARR , 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 12) 
                 
                     
                     IWBAibQGH-ChaRRLGDEINAYYARR , 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein up to 3 of the amino acids are substituted by another amino acid. 
       
     
     
         6 .- 19 . (canceled) 
     
     
         20 . The compound of  claim 1 , wherein the side chains of two amino acids separated by 3 or 6 amino acids are substituted by an intermolecular crosslink. 
     
     
         21 .- 22 . (canceled) 
     
     
         23 . The compound of  claim 20 , wherein the intermolecular crosslink is an alkylene or alkenylene group. 
     
     
         24 .- 30 . (canceled) 
     
     
         31 . The compound of  claim 1 , comprising an amino acid sequence selected from the group consisting of: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 2) 
                 
                     
                   IWBTQGLRRLGDEIXAYYXRR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 3) 
                 
                     
                   IWBAibQGLRRLGDEIXAYYXRR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 4) 
                 
                     
                   IWBAibQGChaRRLGDEIXAYYXRR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 5) 
                 
                     
                   IWBAibQGLQRLGDEIXAYYXRR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 6) 
                 
                     
                   IWBAibQGLDRLGDEIXAYYXRR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 7) 
                 
                     
                   IWBTQGLQRLGDEIXAYYXRR, 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein X is an amino acid whose side chain is replaced with an intermolecular crosslink to another amino acid and wherein up to 6 of the amino acids are substituted by another amino acid. 
       
     
     
         32 .- 48 . (canceled) 
     
     
         49 . The compound of  claim 31 , wherein X is α-4-Pentenyl alanine. 
     
     
         50 . The compound of  claim 4 , wherein the at least one amino acid that is not one of the 20 common, naturally-occurring amino acids is selected from the group consisting of: 4-hydroxyproline, α-4-pentenyl alanine, aminoisobutyric acid (Aib), cyclohexyl alanine (Cha), norleucine, desmosine, gamma-aminobutyric acid, beta-cyanoalanine, norvaline, 4-(E)-butenyl-4(R)-methyl-N-methyl-L-threonine, N-methyl-L-leucine, 1-amino-cyclopropanecarboxylic acid, 1-amino-2-phenyl-cyclopropanecarboxylic acid, 1-amino-cyclobutanecarboxylic acid, 4-amino-cyclopentenecarboxylic acid, 3-amino-cyclohexanecarboxylic acid, 4-piperidylacetic acid, 4-amino-1-methylpyrrole-2-carboxylic acid, 2,4-diaminobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 2-aminoheptanedioic acid, 4-(aminomethyl)benzoic acid, 4-aminobenzoic acid, ortho-, meta-substituted phenylalanines, para-substituted phenylalanines, disubstituted phenylalanines, substituted tyrosines and statine. 
     
     
         51 .- 58 . (canceled) 
     
     
         59 . The compound of  claim 1 , wherein at least one peptide bond is replaced by a bond selected from the group consisting of a retro-inverso bonds (C(O)—NH); a reduced amide bond (NH—CH 2 ); a thiomethylene bond (S—CH 2  or CH 2 —S); an oxomethylene bond (O—CH 2  or CH 2 —O); an ethylene bond (CH 2 —CH 2 ); a thioamide bond (C(S)—NH); a trans-olefin bond (CH═CH); a fluoro substituted trans-olefin bond (CF═CH); a ketomethylene bond (C(O)—CHR) or CHR—C(O) wherein R is H or CH 3 ; and a fluoro-ketomethylene bond (C(O)—CFR or CFR—C(O) wherein R is H or F or CH 3 . 
     
     
         60 .- 62 . (canceled)