# Novel inhibitors of oncogenic p53 mutants for lung cancer therapy.

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $172,376

## Abstract

Project Summary
 Gain-of-function (GOF) p53 mutations are very frequent in all types of chemo- and radio-resistant intractable
lung cancers with poor prognosis. Depletion of endogenous mutant p53 eliminates the tumorigenic phenotype of
many human lung cancer cell lines. Therefore, small molecule inhibitors that specifically inactivate the oncogenic
function of GOF p53 should have a cancer cell-specific efficient impact on many lung cancer patients.
 Using genome wide analyses of lung cancer cells, we have traced the oncogenic properties of GOF p53 to its
ability to transcriptionally activate expression of cell proliferative genes. Our published genetic data showed that
transactivation deficient GOF p53 is defective in tumor formation and proliferation of lung cancer cells. Here we
propose to test a hypothesis that small molecule inhibitors of GOF p53-specific transcriptional activation (GOF
p53TAIn) specifically inhibit proliferation of lung cancer cells and tumors with GOF p53 mutation. Our short-
term goal is to test this hypothesis in cellular and animal models of lung cancer. Our long-term goal is to translate
our findings into novel targeted therapies for human lung cancer.
 In support of our hypothesis, our preliminary studies have identified novel small molecule inhibitors (GOF
p53TAIns) that specifically inhibit GOF p53-driven transcriptional activation sparing Wild-type (WT) p53-
induced transcription and basal transcription. Pilot experiments identified GOF p53TAIns that preferentially
inhibited growth of lung cancer cells with GOF p53, over p53-null lung cancer cells or lung cancer cells with WT
53. One of the GOF p53TAIns, Gloxazone, specifically inhibits GOF p53-induced transcription and cell growth,
and in addition specifically inhibits growth of tumors from xenografts of lung cancer cells with mutant p53 but
not from that of WT p53. The proposed hypothesis will be further tested via the following specific aims:
 Aim 1: Examine identified GOF p53TAIns for their ability to specifically inhibit GOF p53-induced
growth of lung cancer cells inducing cell death. Human lung cancer cell lines spanning different subtypes (non-
small cell, small cell, squamous cell) with or without various GOF p53 mutation (a), matched sets of gene-edited
lung cancer cell lines with GOF p53, WT p53 and p53-null alleles (b), and tumor cells isolated from primary or
passaged patient lung cancer samples (c) will be employed. Ability of GOF p53TAIns to alter GOF p53 stability
will be determined and analysis of mechanism of growth inhibition for selected compounds will be initiated.
 Aim 2: Examine identified GOF p53TAIns for their ability to specifically inhibit GOF p53-driven
tumor growth and induce tumor cell death using mouse models. Three mouse models, tumors from (a)
xenograft of lung cancer cells, implanted subcutaneously or orthotopically, and (b) patient-derived xenografts
(PDX) in immunocompromised mice will be used and (c) inducible GOF p53-dependent lu...

## Key facts

- **NIH application ID:** 10758594
- **Project number:** 5R21CA267971-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Swati P. Deb
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $172,376
- **Award type:** 5
- **Project period:** 2022-12-30 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758594

## Citation

> US National Institutes of Health, RePORTER application 10758594, Novel inhibitors of oncogenic p53 mutants for lung cancer therapy. (5R21CA267971-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10758594. Licensed CC0.

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