Peptidomimetic macrocycles and uses thereof
AssigneeAileron Therapeutics, Inc.
InventorsHubert Chen, David Allen Annis, Yong Chang, Manuel Aivado, Karen Olson, Chris J. Viau
Life of this patent
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Abstract
Methods for treating solid tumor, determined to lack a p53 deactivation mutation, in a subject are provided. Also provided are peptidomimetic macrocycles for use in treatment of a solid tumor, determined to lack a p53 deactivation mutation, in a subject.
Claims53
A method of treating a solid tumor in a human subject in need thereof, wherein the method comprises administering to the human subject 0.5-10 mg of a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof per kilogram body weight of the human subject at least once a week, wherein the solid tumor (i) has a wild type p53 and (ii) is breast cancer, colorectal cancer, endometrial cancer, liver cancer, lung cancer, nerve cancer, multiple myeloma, ovarian cancer, skin cancer, submandibular adenocarcinoma, leiomyosarcoma or thymoma;
- and wherein the peptidomimetic macrocycle (i) binds to a protein in a p53 pathway of the human subject, (ii) comprises an amino acid sequence in any of SEQ ID NOs:
- 10-692 and 1500, and (iii) has a Formula (I):
- wherein:
- each of Xaa3, Xaa5, Xaa6, Xaa7, Xaag, Xaa9, and Xaa10 is individually an amino acid, wherein at least Xaa3, Xaa7, and Xaa10 are the same amino acid as the amino acid of the corresponding position of the sequence:
- Phe3-X4-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12(SEQ ID NO:
- 8);
- each D and E is independently an amino acid;
- each R1 and R2 is independently -H, alkyl, alkenyl, alkynyl, 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;
- each L or L′ is independently a macrocycle-forming linker;
- 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, cycloaryl, or heterocycloaryl, 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, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
- v is an integer from 1-10;
- and
- w is an integer from 0-10.
A method of treating a solid tumor in a human subject in need thereof, wherein the method comprises administering to the human subject 0.32-10 mg of a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof per kilogram body weight of the human subject at least twice a week;
- wherein the solid tumor (i) has a wild type p53 and (ii) is breast cancer, colorectal cancer, endometrial cancer, liver cancer, lung cancer, nerve cancer, multiple myeloma, ovarian cancer, skin cancer, submandibular adenocarcinoma, leiomyosarcoma or thymoma;
- and
- wherein the peptidomimetic macrocycle (i) binds to a protein in a p53 pathway of the human subject, (ii) comprises an amino acid sequence in any of SEQ ID NOs:
- 10-692 and 1500, and (iii) has a Formula (I):
- wherein:
- each of Xaa3, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 is individually an amino acid, wherein at least Xaa3, Xaa7, and Xaa10 are the same amino acid as the amino acid of the corresponding position of the sequence:
- Phe3-X4-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12(SEQ ID NO:
- 8);
- each D and E is independently an amino acid;
- each R1 and R2 are independently -H, alkyl, alkenyl, alkynyl, 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;
- each L or L′ is independently a macrocycle-forming linker;
- 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, cycloaryl, or heterocycloaryl, 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, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
- v is an integer from 1-10;
- and
- w is an integer from 0-10.
Dependencies are inferred from the claim text.