Peptidomimetic macrocycles as modulators of mcl-1

Abstract

The disclosed peptidomimetic macrocycles modulate the activity of MCL-1. Myeloid cell leukemia 1 (MCL-1) is a protein that inhibits cell death. Peptidomimetic macrocycles, pharmaceutical compositions, and methods disclosed herein can be used for the treatment of disease in which MCL-1 is over-expressed, such as cancer. In particular, MCL-1-modulating peptidomimetic macrocycles disclosed herein can be applied in the setting of resistance to BCL-2 family inhibitors, which is often engendered by MCL-1 over-expression or hyper-activation.

1 - 162 . (canceled) 
     
     
         163 . A peptidomimetic macrocycle of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein 
 each A, B, C, D, and E is independently an amino acid and the terminal D and E independently optionally include a capping group; 
 L is a macrocycle-forming linker; 
 L′ is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, optionally substituted with R 5 , or a bond; R 1  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each being optionally substituted with halo-; or R 1  and L′ together with the atom to which both R 1  and L′ are bound form a ring; 
 L″ is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, optionally substituted with R 5 , or a bond; R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each being optionally substituted with halo-; or R 2  and L″ together with the atom to which both R 2  and L″ are bound form a ring; 
 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, aryl, or heteroaryl, each being 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, aryl, or heteroaryl, each being optionally substituted with R 5 , or part of a cyclic structure with an E residue; 
 v is 1-10; 
 w is an integer from 1-1000; 
 u is 1; and 
 each x, y, and z is an integer such that x+y+z is 3; 
 wherein [A] x -[B] y -[C] z  comprises an isoleucine (Ile) and an aspartic acid (Asp) and [E] w  comprises an arginine (Arg) and a histidine (His). 
 
     
     
         164 . The peptidomimetic macrocycle of  claim 163 , wherein R 1  and L′ together with the atom to which both R 1  and L′ are bound form a ring. 
     
     
         165 . The peptidomimetic macrocycle of  claim 163 , wherein R 2  and L″ together with the atom to which both R 2  and L″ are bound form a ring. 
     
     
         166 . The peptidomimetic macrocycle of  claim 163 , wherein the peptidomimetic macrocycle comprises an α-helix. 
     
     
         167 . The peptidomimetic macrocycle of  claim 163 , wherein -[A] x -[B] y -[C] z - is -Ile-[B] 1 -Asp-. 
     
     
         168 . The peptidomimetic macrocycle of  claim 163 , wherein B is a hydrophobic amino acid. 
     
     
         169 . The peptidomimetic macrocycle of  claim 163 , wherein [E] w  comprises two arginines. 
     
     
         170 . The peptidomimetic macrocycle of  claim 163 , wherein R 2  is methyl. 
     
     
         171 . The peptidomimetic macrocycle of  claim 163 , wherein both R 7  and R 8  are hydrogen. 
     
     
         172 . The peptidomimetic macrocycle of  claim 163 , wherein w is an integer from 1-15. 
     
     
         173 . The peptidomimetic macrocycle of  claim 163 , wherein L′ and L″ is each independently alkylene, alkenylene, or alkynylene. 
     
     
         174 . A pharmaceutical composition comprising
 (i) a peptidomimetic macrocycle of Formula (I):   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein 
 each A, B, C, D, and E is independently an amino acid and the terminal D and E independently optionally include a capping group; 
 L is a macrocycle-forming linker; 
 L′ is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, optionally substituted with R 5 , or a bond; R 1  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each being optionally substituted with halo-; or R 1  and L′ together with the atom to which both R 1  and L′ are bound form a ring; 
 L″ is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, optionally substituted with R 5 , or a bond; R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each being optionally substituted with halo-; or R 2  and L″ together with the atom to which both R 2  and L″ are bound form a ring; 
 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, aryl, or heteroaryl, each being 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, aryl, or heteroaryl, each being optionally substituted with R 5 , or part of a cyclic structure with an E residue; 
 v is 1-10; 
 w is an integer from 1-1000; 
 u is 1; and 
 each x, y, and z is an integer such that x+y+z is 3; 
 wherein [A] x -[B] y -[C] z  comprises an isoleucine (Ile) and an aspartic acid (Asp) and [E] w  comprises an arginine (Arg) and a histidine (His); and 
 (ii) a pharmaceutically-acceptable carrier. 
 
     
     
         175 . A method of treating a cancer in a subject, the method comprising administering to the subject suffering from the cancer a therapeutically-effective amount of a peptidomimetic macrocycle of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein 
 each A, B, C, D, and E is independently an amino acid and the terminal D and E independently optionally include a capping group; 
 L is a macrocycle-forming linker; 
 L′ is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, optionally substituted with R 5 , or a bond; R 1  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each being optionally substituted with halo-; or R 1  and L′ together with the atom to which both R 1  and L′ are bound form a ring; 
 L″ is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, optionally substituted with R 5 , or a bond; R 2  is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each being optionally substituted with halo-; or R 2  and L″ together with the atom to which both R 2  and L″ are bound form a ring; 
 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, aryl, or heteroaryl, each being 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, aryl, or heteroaryl, each being optionally substituted with R 5 , or part of a cyclic structure with an E residue; 
 v is 1-10; 
 w is an integer from 1-1000; 
 u is 1; and 
 each x, y, and z is an integer such that x+y+z is 3; 
 wherein [A] x -[B] y -[C] z  comprises an isoleucine (Ile) and an aspartic acid (Asp) and [E] w  comprises at an arginine (Arg) and a histidine (His). 
 
     
     
         176 . The method of  claim 176 , wherein R 1  and L′ together with the atom to which both R 1  and L′ are bound form a ring. 
     
     
         177 . The method of  claim 176 , wherein R 2  and L″ together with the atom to which both R 2  and L″ are bound form a ring. 
     
     
         178 . The method of  claim 176 , wherein the peptidomimetic macrocycle comprises an a-helix. 
     
     
         179 . The method of  claim 176 , wherein -[A] x -[B] y -[C] z - is -Ile-[B] 1 -Asp-. 
     
     
         180 . The method of  claim 176 , wherein the cancer is colorectal cancer, liver cancer, breast cancer, prostate cancer, uterine cancer, or lung cancer. 
     
     
         181 . The method of  claim 176 , further comprising administering to the subject an additional therapy to treat the cancer.