# Mechanisms of mutant p53 reactivation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $537,081

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10885197
- **Project number:** 5R01CA283462-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Peter Kaiser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $537,081
- **Award type:** 5
- **Project period:** 2023-07-10 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885197

## Citation

> US National Institutes of Health, RePORTER application 10885197, Mechanisms of mutant p53 reactivation (5R01CA283462-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10885197. Licensed CC0.

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