# Developing corrector small molecules for reactivation of mutant p53 in cancer

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $210,003

## 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 associated with p53 are missense mutations that affect one of six hotspot sites in the DNA
binding domain. These cancers express full length p53 that has lost tumor suppressor activity, but acquired
gain-of-function oncomorphic properties that provide selective advantage to cancer cells.
Therapeutic approaches targeting p53 are challenging and require reactivation of mutated p53. Developing
such reactivation or corrector drugs is 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. However, one can argue that genuine p53 corrector drugs have not yet been tested in the clinic,
because in vivo the available compounds (i.e. APR-246 and other thiol reactive molecules) are most likely not
acting on mutant p53, but rather exploit redox-sensitivity of cells expressing p53 mutants. Development of
genuine p53 mutant corrector drugs that bind p53 and restore a wild-type like conformation/activity in p53
cancer mutants, thus remains a crucial goal with potentially very high impact.
We have developed a small molecule series that binds the L1/S3 pocket of mutant p53 and thereby restores
DNA binding activity of mutant p53 in a reconstituted purified in vitro system. These results are reflected in
induction of p53 target gene expression 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 solid 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 can restore tumor
suppressor activity in p53 hotspot mutants. However, these compounds act in the low micromolar range in cell
culture systems and activity needs to be improved to generate lead compounds for drug development. We
propose two parallel approaches to achieve this goal.
This proposal will generate promising lead compounds for mutant p53 corrector drug development.

## Key facts

- **NIH application ID:** 10512976
- **Project number:** 1R21CA267495-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Peter Kaiser
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $210,003
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10512976

## Citation

> US National Institutes of Health, RePORTER application 10512976, Developing corrector small molecules for reactivation of mutant p53 in cancer (1R21CA267495-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10512976. Licensed CC0.

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