# Development of p300/CBP histone acetyltransferase inhibitors for oncogene-driven cancers

> **NIH NIH R01** · BROAD INSTITUTE, INC. · 2022 · $682,670

## Abstract

Project Summary:
Oncogene mutations frequently drive malignant transformation through inappropriate activation of regulatory
kinases, and inhibitors that disrupt oncogenic phosphorylation have transformed care for subsets of cancer
patients. Despite these successes, kinases are a small fraction of known oncogenes. In particular, several
transcriptional factor oncogenes are essential for tumor initiation, progression and maintenance. In a few cases,
targeting transcription factor oncogenes, such as estrogen, androgen and retinoic acid receptors, has led to
clinically meaningful responses. However, direct targeting of most transcription factors has proven challenging.
An alternative approach to directly targeting oncogenic transcription factors is to inhibit upstream epigenetic
mechanisms regulating chromatin state. Indeed, many epigenetic regulators are recurrently somatically mutated,
and several small molecules targeting chromatin regulators have been shown to abrogate tumor growth. In
preliminary studies, we performed a gene expression-based screen to identify small molecules that inhibit the
activity of TMPRSS2-ERG, a fusion oncogene leading to aberrant transcription in prostate cancer, and identified
BRD4683, a highly potent inhibitor of p300 and CREB binding protein (CBP) histone acetyl transferase (HAT)
activity. We have solved the structure of BRD4683 in complex with p300 and confirmed that inhibition of
p300/CBP HAT activity is specifically required for survival of transcription factor-driven human cancer cell lines.
Despite serving as a useful tool compound, BRD4683 has several chemical liabilities that limit its potential for
drug development.
 We thus used BRD4683 to develop and validate a high-throughput and cost-effective biochemical screen
for discovery of additional novel small molecule p300/CBP HAT inhibitors as well as a cascade of follow up-
assays to eliminate false positives and prioritize chemically tractable molecules. In this project, we propose to
identify new p300/CBP inhibitors and to systematically identify tumor subtypes dependent on combined
p300/CBP HAT activity. In Aim 1, we will perform a high throughput biochemical screen of more than 800,000
compounds to identify new p300/CBP HAT inhibitors. In Aim 2, we will validate novel p300/CBP candidates using
three complementary assays to identify inhibitors an IC50 of at least 10 µM. These assays will not only confirm
inhibitor specificity but will also validate biochemical activity in cells. In Aim 3, we will perform iterative medicinal
chemistry with the goal of identifying lead candidates. In parallel to these studies, we will perform both chemical
and genetic experiments to systematically identify tumor subtypes that depend on p300/CBP HAT activity for cell
fitness (Aim 4).
 To perform these studies, we have assembled a multidisciplinary research team with the necessary
experience and expertise in cancer biology, structural biology, medicinal chemistry and drug develo...

## Key facts

- **NIH application ID:** 10344246
- **Project number:** 1R01CA266642-01
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** William C. Hahn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $682,670
- **Award type:** 1
- **Project period:** 2022-05-25 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10344246

## Citation

> US National Institutes of Health, RePORTER application 10344246, Development of p300/CBP histone acetyltransferase inhibitors for oncogene-driven cancers (1R01CA266642-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10344246. Licensed CC0.

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