Peptidomimetic macrocycles as modulators of MCL-1
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-038/00
A61P-035/00
C07K-007/06
출원번호
US-0259947
(2016-09-08)
등록번호
US-10023613
(2018-07-17)
발명자
/ 주소
Guerlavais, Vincent
Feyfant, Eric
출원인 / 주소
AILERON THERAPEUTICS, INC.
대리인 / 주소
Wilson Sonsini Goodrich & Rosati
인용정보
피인용 횟수 :
1인용 특허 :
167
초록▼
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-expres
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.
대표청구항▼
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-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-]; [A]x[B]y-[C]z comprises the sequence I-G-D;each
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-L3-CO—], [—NH-L3-SO2—], or [—NH-L3-]; [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 R5, or a bond, or together with R1 and the atom to which both R1 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 R5, or a bond, or together with R2 and the atom to which both R2 and L″ are bound forms a ring;each R1 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 R1 and L′ are bound forms a ring;each R2 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 R2 and L″ are bound forms a ring;each R3 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, aryl, or heteroaryl, each being optionally substituted with R5;each L3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or [—R4—K—R4—]n, each being optionally substituted with R5;each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;each K is independently O, S, SO, SO2, CO, CO2, or CONR3;each n is independently an integer from 1-5;each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope, or a therapeutic agent;each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope, or a therapeutic agent;each R7 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, each being optionally substituted with R5, or part of a cyclic structure with a D residue;each R8 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, each being optionally substituted with R5, 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; andthe sum of x+y+z is 3, 4, 5, 6, 7, 8, 9, or 10, ora 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 R1 and R2 are H. 10. The peptidomimetic macrocycle of claim 1, wherein R1 and R2 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 -L1-L2-, and L1 and L2 are independently alkylene, alkenylene, or alkynylene. 16. The peptidomimetic macrocycle of claim 1, wherein L is the formula -L1-L2-, and L1 and L2 are independently C3-C10 alkylene or C3-C10 alkenylene. 17. The peptidomimetic macrocycle of claim 1, wherein L is the formula -L1-L2-, and L1 and L2 are independently C3-C6 alkylene or C3-C6 alkenylene.
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