Peptidomimetic macrocycles and uses thereof
Inventors
Chen, Hubert • Annis, David Allen • Chang, Yong • Aivado, Manuel • Olson, Karen • Viau, Chris J.
Assignees
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Publication Number
US-10471120-B2
Publication Date
2019-11-12
Expiration Date
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.
Core Innovation
The disclosure relates to a method of treating a solid tumor in a human subject in need thereof by administering a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof. The solid tumor has wild type p53 and is selected from breast cancer, colorectal cancer, endometrial cancer, liver cancer, lung cancer, nerve cancer, multiple myeloma, ovarian cancer, skin cancer, submandibular adenocarcinoma, leiomyosarcoma, or thymoma. The peptidomimetic macrocycle binds to a protein in a p53 pathway of the human subject, and treatment is characterized by p53 pathway reactivation.
The peptidomimetic macrocycle comprises an amino acid sequence in any of SEQ ID NOs: 10-692 and 1500 and has a Formula (I) with defined amino-acid position constraints. The structural framework includes amino acid definitions, linker-forming linker L or L′, capping groups, substituents R1, R2, R5, R6, R7, and R8, and variable parameters v and w. The described framework also includes correspondence to the sequence Phe3-X4-His5-Tyr6-Trp7-Ala8-Gln9-Leu10-X11-Ser12 (SEQ ID NO: 8) and related sequence-position constraints.
The supporting description states that the approach disrupts p53-MDM2/MDMX interactions by macrocycles that bind to MDM2/MDMX, thereby reactivating p53 signaling including p53 and p21 and inducing apoptosis. The disclosure further states that p53 status may be confirmed by DNA sequencing, RNA array based testing, RNA analysis, or PCR, and that biomarker detection with PK/PD via dynamic sampling is associated with the treatment description.
Claims Coverage
The consolidated claim coverage includes 2 independent claims. Both independent claims cover administering a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof to treat a solid tumor with wild type p53, where the macrocycle binds to a protein in a p53 pathway and is structurally defined by an amino acid sequence set and Formula (I). The main differences between the independent claims are the dosage range and dosing frequency.
Treating a wild type p53 solid tumor with a peptidomimetic macrocycle of Formula (I)
Administering a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof to a human subject in need thereof, where the solid tumor has wild type p53 and is selected from breast cancer, colorectal cancer, endometrial cancer, liver cancer, lung cancer, nerve cancer, multiple myeloma, ovarian cancer, skin cancer, submandibular adenocarcinoma, leiomyosarcoma, or thymoma; the peptidomimetic macrocycle binds to a protein in a p53 pathway, comprises an amino acid sequence in any of SEQ ID NOs: 10-692 and 1500, and has Formula (I) with defined amino-acid position constraints, D and E amino acid definitions, R1/R2 definitions, macrocycle-forming linker L or L′, and variable side-chain definitions, with v and w ranges.
Once-weekly administration dosage of Formula (I) peptidomimetic macrocycle
Administering 0.5-10 mg per kilogram body weight at least once a week to treat a wild type p53 solid tumor with the same peptidomimetic macrocycle, sequence, Formula (I), and p53 pathway binding requirements.
At-least-twice-weekly administration dosage of Formula (I) peptidomimetic macrocycle
Administering 0.32-10 mg per kilogram body weight at least twice a week to treat a wild type p53 solid tumor with the same peptidomimetic macrocycle, sequence, Formula (I), and p53 pathway binding requirements.
Overall, the claim coverage is centered on treating a human solid tumor having wild type p53 using a peptidomimetic macrocycle that binds to a protein in a p53 pathway and conforms to Formula (I) with specified sequence, linker, and substituent constraints, with the independent claims differing mainly in dosing amount and dosing frequency.
Stated Advantages
Improved alpha-helicity.
Higher melting temperature (Tm).
Protease resistance.
Ex vivo stability.
Cellular penetrability and cellular efficacy.
Improved protein binding performance as evaluated by fluorescence polarization assay (FPA) and affinity selection-mass spectrometry (ALIS/SEC-LC-MS).
Reactivation of the p53 pathway by disrupting p53-MDM2/MDMX interactions, leading to p21 and apoptosis in tumors.
decreased proliferation
increased p21/apoptosis
reduced tumor volume
increased survival
Documented Applications
Treating a solid tumor in a human subject with wild type p53, including breast cancer, colorectal cancer, endometrial cancer, liver cancer, lung cancer, nerve cancer, multiple myeloma, ovarian cancer, skin cancer, submandibular adenocarcinoma, leiomyosarcoma, and thymoma.
Therapy application where peptidomimetic macrocycles bind a protein in a p53 pathway to disrupt p53-MDM2/MDMX interactions and reactivate the p53 pathway.
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