Peptidomimetic macrocycles

Patent metadata

Field	Value
Publication number	US-10213477-B2
Application number	US-201615229517-A
Country	US
Kind code	B2
Filing date	Aug 5, 2016
Priority date	Feb 15, 2012
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

Provided herein are peptidomimetic macrocycles containing amino acid sequences with at least two modified amino acids that form an intramolecular cross-link that can help to stabilize a secondary structure of the amino acid sequence. Suitable sequences for stabilization include those with homology to the p53 protein. These sequences can bind to the MDM2 and/or MDMX proteins. Also provided herein are methods of using such macrocycles for the treatment of diseases and disorders, such as cancers or other disorders characterized by a low level or low activity of a p53 protein or high level of activity of a MDM2 and/or MDMX protein.

First claim

What is claimed is:

1. A method for treating a cancer, comprising administering to a subject with the cancer a therapeutically effective amount of a pharmaceutical product comprising:
(a) a first therapeutic agent comprising an inhibitor of an interaction between p53 and MDM2 and/or an inhibitor of an interaction between p53 and MDMX, and
(b) a second therapeutic agent comprising a chemotherapeutic agent;
wherein the first therapeutic agent is a peptidomimetic macrocycle comprising an amino acid sequence with at least about 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ IP NOs: 10-457, or pharmaceutically acceptable salt thereof; and wherein the peptidomimetic macrocycle has a Formula:

wherein:
each of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaa 9 , and Xaa 10 is independently an amino acid, wherein at least three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7 , Xaa 8 , Xaa 9 , and Xaa 10 are the same amino acids as the amino acid at the corresponding position of the sequence Phe 3 -X 4 -His 5 - Tyr 6 -Trp 7 -Ala 8 -Gln 9 -Leu 10 -X 11 -Ser 12 (SEQ ID NO: 8) or Phe 3 -X 4 -Glu 5 -Tyr 6 -Trp 7 -Ala 8 -Gln 9 -Leu 10 /Cba 10 -X 11 -Ala 12 (SEQ ID NO: 9), wherein each X 4 and X 11 is independently an amino acid:
each D is independently an amino acid;
each E is independently an amino acid selected from the group consisting of Ala (alanine), D-Ala (D-alanine), Aib (α-aminoisobutyric acid), Sar (N-methyl glycine), and Ser (serine);
R 1 and R 2 are independently -H, alkyl, alkenyl, alkyenyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;
L and L′ are independently a macrocycle-forminig linker;
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, alkenyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
R 7 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R 5 , or part of a cyclic structure with a D residue;
R 8 is -H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with R 5 , or part of a cyclic structure with an E residue;
v is an integer from 1-10;
w is an integer from 3-10; and
and wherein the cancer is head and neck cancer, melanoma, lung cancer, breast cancer, glioma, or a hematological cancer.

2. The method of claim 1 , wherein the first therapeutic agent and the second therapeutic agent are administered separately or as a single composition.

3. The method of claim 1 , wherein the first therapeutic agent, the second therapeutic agent, or both are administered intravenously, intraperitoneally or subcutaneously.

4. The method of claim 1 , wherein the second therapeutic agent is administered at a dosage of between 1% to 100% of a dosage of the second therapeutic agent normally administered in a monotherapy regimen.

5. The method of claim 1 , wherein the cancer is selected from the group consisting of head and neck cancer, melanoma, lung cancer, breast cancer, and glioma.

6. The method of claim 1 , wherein the cancer is a hematological cancer.

7. The method of claim 6 , wherein the hematological cancer is acute myelogenous leukemia (AML).

8. The method of claim 1 , wherein the second therapeutic agent is selected from the group consisting of a small molecule, a polypeptide, and an oligonucleotide.

9. The method of claim 1 , wherein L and L′ are independently a macrocycle-forming linker of the formula -L 1 -L 2 -, wherein:
L 1 and L 2 are 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, or heterocycloalkylene;
each K is independently O, SO, SO 2 , CO, CO 2 , or CONR 3 ; and each n is independently an integer from 1-5.

10. The method of claim 1 , wherein L is alkylene, alkenylene, or alkynylene.

11. The method of claim 1 , wherein R 1 and R 2 are independently -H or alkyl.

12. The method of claim 1 , wherein v is an integer from 2-5.

13. The method of claim 1 , wherein w is an integer from 3-6.

14. The method of claim 1 , wherein [D] v is -Leu 1 -Thr 2 .

15. The method of claim 1 , wherein each E is independently Ser or Ala.

16. The method of claim 5 , wherein the cancer is head and neck cancer.

17. The method of claim 5 , wherein the cancer is melanoma.

18. The method of claim 5 , wherein the cancer is lung cancer.

19. The method of claim 5 , wherein the cancer is breast cancer.

20. The method of claim 5 , wherein the cancer is glioma.

21. The method of claim 6 , wherein the hematological cancer is lymphoma.

Assignees

• Aileron Therapeutics Inc

Inventors

• Guerlavais Vincent
• Elkin Carl
• Nash Huw M
• Sawyer Tomi K
• Graves Bradford J
• Feyfant Eric

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• C07K14/4746 Primary

  p53 · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title