Therapeutic peptidomimetic macrocycles

Abstract

The present invention provides biologically active peptidomimetic macrocycles for the treatment of cell proliferative disorders such as cancer and immunoproliferative disease.

What is claimed is: 
     
         1 - 87 . (canceled) 
     
     
         88 . A peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises a polypeptide and a crosslinker connecting two amino acid residues of the polypeptide and has a formula of: 
       
         
           
           
               
               
           
         
         wherein: 
         the polypeptide is at least 60% identical to an amino acid sequence IWIAQALRRIGDEFNAYYARR (SEQ ID NO:120); 
         “AA” is a natural or non-natural amino acid side chain; 
         “ ” is [D] v  or [E] w ; 
         each D and E is independently a natural or non-natural amino acid; 
         each v and w is independently an integer from 1-1000; 
         each R 1  and R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each of which except —H is unsubstituted or substituted with halo-; 
         each L is independently a crosslinker of a formula -L 1 -L 2 - or a formula -L 1 -L 2 -L 3 -; and 
         each L 1  and L 2  and L 3  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene. 
       
     
     
         89 . The peptidomimetic macrocycle of  claim 88 , wherein the peptidomimetic macrocycle is at least 80% identical to the amino acid sequence. 
     
     
         90 . The peptidomimetic macrocycle of  claim 88 , wherein the peptidomimetic macrocycle comprises an alpha helix. 
     
     
         91 . The peptidomimetic macrocycle of  claim 88 , wherein L is the formula -L 1 -L 2 -. 
     
     
         92 . The peptidomimetic macrocycle of  claim 91 , wherein each L 1  and L 2  is independently C 3 -C 6  alkylene. 
     
     
         93 . The peptidomimetic macrocycle of  claim 91 , wherein each L 1  and L 2  is independently C 3 -C 6  alkenylene. 
     
     
         94 . The peptidomimetic macrocycle of  claim 88 , wherein L is the formula -L 1 -L 2 -L 3 -, and each L 1  and L 3  is independently C 3 -C 6  alkylene, and L 2  is heteroarylene. 
     
     
         95 . The peptidomimetic macrocycle of  claim 88 , wherein at least one of R 1  and R 2  is alkyl, unsubstituted or substituted with halo-. 
     
     
         96 . The peptidomimetic macrocycle of  claim 88 , wherein R 1  and R 2  are independently alkyl, unsubstituted or substituted with halo-. 
     
     
         97 . The peptidomimetic macrocycle of  claim 88 , wherein at least one of R 1  and R 2  is methyl. 
     
     
         98 . The peptidomimetic macrocycle of  claim 88 , wherein R 1  and R 2  are methyl. 
     
     
         99 . The peptidomimetic macrocycle of  claim 88 , wherein R 1  and R 2  are H. 
     
     
         100 . A method of treating a disorder in a human subject in need thereof, comprising administering to the subject a peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises a polypeptide and a crosslinker connecting two amino acid residues of the polypeptide and has a formula of: 
       
         
           
           
               
               
           
         
         wherein: 
         the polypeptide is at least 60% identical to an amino acid sequence IWIAQALRRIGDEFNAYYARR (SEQ ID NO:120); 
         “AA” is a natural or non-natural amino acid side chain; 
         “ ” is [D] v  or [E] w ; 
         each D and E is independently a natural or non-natural amino acid; 
         each v and w is independently an integer from 1-1000; 
         each R 1  and R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each of which except —H is unsubstituted or substituted with halo-; 
         each L is independently a crosslinker of the formula -L 1 -L 2 - or the formula -L 1 -L 2 -L 3 -; and 
         each L 1  and L 2  and L 3  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene. 
       
     
     
         101 . The method of  claim 100 , wherein the disorder is a cancer. 
     
     
         102 . The method of  claim 101 , wherein the cancer is an ovarian cancer, skin cancer, prostate cancer, renal cancer, breast cancer, pancreatic cancer, small-cell lung cancer, colon cancer, liver cancer, Multiple myeloma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL) of T cell lineage or B cell lineage or mixed lineage, Chronic lymphocytic leukemia (CLL), Ph+ acute lymphocytic leukemia, Cutaneous T cell lymphoma (CTCL), Acute myelocytic leukemia (AML), Chronic Myelocytic leukemia, or follicular lymphoma. 
     
     
         103 . The method of  claim 101 , wherein the cancer is resistant to ABT-737 or an analog thereof. 
     
     
         104 . The method of  claim 100 , wherein the disorder is a metabolic disorder. 
     
     
         105 . The method of  claim 100 , wherein the disorder is an immunoproliferative disorder. 
     
     
         106 . The method of  claim 100 , wherein the administering is in conjunction with a standard method of care that is chemotherapy, radiation therapy, or surgery. 
     
     
         107 . A method of preparing a peptidomimetic macrocycle, comprising:
 (a) preparing a peptidomimetic macrocycle by crosslinking two amino acid residues of a polypeptide to stabilize a secondary structure of the peptidomimetic macrocycle;   (b) testing the peptidomimetic macrocycle for a reduced antibody response in an in vivo assay as compared to a corresponding uncrosslinked polypeptide; and   (c) selecting the tested peptidomimetic macrocycle as the therapeutic peptidomimetic macrocycle if the tested peptidomimetic macrocycle has a reduced immune response relative to the corresponding uncrosslinked polypeptide; and   wherein the peptidomimetic macrocycle has a formula of:   
       
         
           
           
               
               
           
         
         wherein: 
         the polypeptide is at least 60% identical to an amino acid sequence 
       
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 120) 
                 
                     
                   IWIAQALRRIGDEFNAYYARR; 
                 
             
                
                
               
            
           
         
         “AA” is a natural or non-natural amino acid side chain; 
         “ ” is [D] v  or [E] w ; 
         each D and E is independently a natural or non-natural amino acid; 
         each v and w is independently an integer from 1-1000; 
         each R 1  and R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each of which except —H is unsubstituted or substituted with halo-; 
         each L is independently a crosslinker of the formula -L 1 -L 2 - or the formula -L 1 -L 2 -L 3 -; and 
         each L 1  and L 2  and L 3  is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene.