# Transcriptional Mechanism of BRD4 in Solid Tumor

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $387,731

## Abstract

PROJECT SUMMARY
BRD4, a major BET (bromo and extra terminal) family transcription regulator, plays a pivotal role
in ordered gene transcription in chromatin through its characteristic tandem acetyl-lysine binding
bromodomains (BrDs). BRD4 is widely recognized as a promising anticancer drug target from
studies using BET BrD inhibitors, some of which are being evaluated in human clinical trials for
cancer. However, BET inhibitors are mostly effective in hematopoietic cancers, but much less
so in solid tumors including breast cancers. The opening question is why chemical inhibition of
this general transcription regulator affects only a limited number of genes and is highly sensitive
to cell- and tumor-types. Our recent studies suggest that the mechanism by which BRD4
regulates transcription in chromatin is likely far more complex than the current simplistic view of
BrDs binding to acetylated histones and transcription proteins and influenced by context-
dependent coordinated activities of its tandem BrDs. We show that a conformationally optimized
bivalent BET BrD inhibitor that simultaneously inhibits the tandem BrDs of BRD4 affords
sustained repression of BRD4 transcriptional activity by blocking its association with enhancer/
mediator proteins with potency far superior to monovalent BET inhibitors, resulting in inhibition
of proliferation of solid tumor cells including a panel of triple negative breast cancer (TNBC)
cells and even JQ1 resistant TNBC cells. Our study provides direct experimental evidence on
the cell-type and context dependent BRD4 functions in cancers and suggests a new therapeutic
strategy to maximally control BRD4 activity required for rapid solid tumor cell proliferation such
as the devastating TNBC that currently lacks targeted therapy. Motivated by our promising new
findings, in this project, we will develop next-generation BRD4-selective bivalent BrD inhibitors
and characterize the transcriptional mechanism and therapeutic potential of BRD4 as a new
targeted treatment for TNBC.

## Key facts

- **NIH application ID:** 9883764
- **Project number:** 5R01CA239165-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ming-Ming Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,731
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883764

## Citation

> US National Institutes of Health, RePORTER application 9883764, Transcriptional Mechanism of BRD4 in Solid Tumor (5R01CA239165-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9883764. Licensed CC0.

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