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Mechanisms of mutant p53 reactivation

突变体 p53 重新激活的机制

基本信息

批准号：
10719196
负责人：
Peter Kaiser
金额：
$ 49.81万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-10 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10719196
关键词：
Academia Affect Alleles Amino Acids Animal Model Apoptosis Binding Bioinformatics Biological Biology Biophysics Biotechnology Cancer Patient Cell Cycle Arrest Cell Proliferation Cells Chemicals Clinic Clinical Trials Collection Crystallography DNA DNA Binding DNA Binding Domain Development Diagnosis Exposure to Future Gene Expression Genes Genetic Genetic Induction Genetic study Goals Human In Vitro Knowledge Length Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Mass Spectrum Analysis Missense Mutation Molecular Molecular Conformation Mutate Mutation Oxidation-Reduction Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Positioning Attribute Process Property Proteins Reporting Series Site Structure Structure-Activity Relationship System TP53 gene Testing Therapeutic Tumor Suppression Tumor Suppressor Proteins United States cancer cell cancer therapy crosslink drug development drug-like compound experience experimental study gain of function in vivo inhibitor mutant novel therapeutic intervention pharmacologic prevent programs reconstitution small molecule success targeted cancer therapy therapeutic protein therapeutic target tool translational therapeutics triple-negative invasive breast carcinoma tumor tumor growth tumor progression

项目摘要

PROJECT SUMMARY The tumor suppressor protein p53 is the most frequently mutated protein in human cancers. About 600,000 new cancer patients in the United States are diagnosed each year with tumors expressing mutated p53. Most of the mutations are missense mutations that affect one of six hotspot sites in the p53 DNA binding domain. These cancers express full length p53 that has lost tumor suppressor activity, but has acquired gain-of-function oncomorphic properties that provide selective advantage to cancer cells. The large number of affected cancers make p53 an exquisite target for cancer therapy. However, therapeutic approaches require reactivation of mutated p53. Developing “reactivation or corrector drugs” is challenging in itself, but further complicated by very limited experience in pharma, biotech, and academia in this domain. These challenges in exploring novel therapeutic approaches by developing p53 corrector drugs have led to very slow, and limited success in clinical trials with proposed p53 reactivator compounds. It recently emerged that several of the reported compounds are likely not acting on mutant p53 in vivo, but rather exploit redox- sensitivity of cells expressing p53 mutants. Development of bona fide p53 mutant corrector drugs that bind p53 and restore a wild-type like conformation/activity in p53 cancer mutants, thus remains a central goal with potentially very high impact. To achieve this goal mechanistic understanding of the p53 cancer mutant reactivation process is essential, but currently mostly lacking due to the lack of genuine p53 corrector molecules with the exception of compounds developed specifically for the relatively rare p53-Y220C allele. We have extensively studied genetic and pharmacological p53 reactivation. We found that Intragenic rescue mutations and small molecules we are developing induce a similar conformational change and stabilize an active conformation of p53 hotspot mutants. Although reactivation mutations have no direct therapeutic potential, they help in our understanding of p53 mutant reactivation mechanisms and can guide corrector drug development. Using information obtained from reactivating second-site mutations, we have developed tool compounds that bind mutant p53 and thereby restore DNA binding activity of mutant p53 in a reconstituted purified in vitro system. p53 target genes are induced when cells harboring p53 hotspot mutants are exposed to these compounds. Furthermore, cell proliferation is halted and apoptosis is induced in a p53 mutant dependent manner. Importantly, growth of tumors carrying p53 mutants is blocked by this compound series in animal models. Tumors lacking p53 or expressing wild-type p53 are not affected by such treatment. These compounds provide strong support for feasibility to develop drug-like molecules that act as genuine p53 mutant correctors. We now propose to use these tool compounds as well as well-characterized rescue mutations to develop detailed molecular understanding of the reactivation process for p53 hotspot mutants. Findings from these studies will be essential to jump start the development of chemically diverse p53 corrector drugs.

项目总结