Peptidomimetic macrocycles as modulators of MCL-1
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. A peptidomimetic macrocycle of Formula (Ic):
wherein:
each A, C, D, and E is independently a natural or non-natural amino acid;
each B is independently a natural or non-natural amino acid, amino acid analog,
[—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
[A] x [B] y -[C] z comprises the sequence I-G-D;
each L is independently a macrocycle-forming linker;
each L′ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each being optionally substituted with R 5 , or a bond, or together with R 1 and the atom to which both R 1 and L′ are bound forms a ring;
each L″ is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each being optionally substituted with R 5 , or a bond, or together with R 2 and the atom to which both R 2 and L″ are bound forms a ring;
each R 1 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each being optionally substituted with halo, or together with L′ and the atom to which both R 1 and L′ are bound forms a ring;
each R 2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, each being optionally substituted with halo-, or together with L″ and the atom to which both R 2 and L″ are bound forms a ring;
each R 3 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, aryl, or heteroaryl, each being optionally substituted with R 5 ;
each L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, 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 n is independently an integer from 1-5;
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 an integer from 1-1000,
w is an integer from 2-1000 and at least two E amino acids are His residues;
u is an integer from 1-10; and
the sum of x+y+z is 3, 4, 5, 6, 7, 8, 9, or 10, or
a pharmaceutically-acceptable salt thereof.
2. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises two crosslinks, wherein a first crosslink is of a first pair of amino acid residues, and a second crosslink is of a second pair of amino acid residues.
3. The peptidomimetic macrocycle of claim 2 , wherein the first pair of amino acid residues and the second pair of amino acid residues do not share a common amino acid residue.
4. The peptidomimetic macrocycle of claim 2 , wherein the first pair of amino acid residues and the second pair of amino acid residues share one common amino acid residue.
5. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises a helix.
6. The peptidomimetic macrocycle of claim 1 , wherein the peptidomimetic macrocycle comprises an α-helix.
7. The peptidomimetic macrocycle of claim 1 , wherein v is an integer from 1 to 15.
8. The peptidomimetic macrocycle of claim 1 , wherein L is
9. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are H.
10. The peptidomimetic macrocycle of claim 1 , wherein R 1 and R 2 are methyl.
11. A pharmaceutical composition comprising a peptidomimetic macrocycle of claim 1 and a pharmaceutically-acceptable carrier.
12. A method of treating a disorder, the method comprising administering to a subject in need thereof a therapeutically-effective amount of the peptidomimetic macrocycle of claim 1 .
13. The method of claim 12 , wherein the disorder is a cancer.
14. The method of claim 13 , wherein the cancer is resistant to a BCL-2 inhibitor therapy.
15. The peptidomimetic macrocycle of claim 1 , wherein L is the formula -L 1 -L 2 -, and L 1 and L 2 are independently alkylene, alkenylene, or alkynylene.
16. The peptidomimetic macrocycle of claim 1 , wherein L is the formula -L 1 -L 2 -, and L 1 and L 2 are independently C 3 -C 10 alkylene or C 3 -C 10 alkenylene.
17. The peptidomimetic macrocycle of claim 1 , wherein L is the formula -L 1 -L 2 -, and L 1 and L 2 are independently C 3 -C 6 alkylene or C 3 -C 6 alkenylene.