# BRD4 Inhibition for Opioid Pharmacotherapy

> **NIH NIH U18** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2020 · $237,000

## Abstract

PROJECT SUMMARY
The U.S. is reeling from a public health crisis driven by the misuse of prescription opioids (e.g., oxycodone),
heroin and fentanyl derivatives. Medication-assisted treatment (MAT) aids in reducing mortality, opioid
withdrawal, intake and opioid-seeking behaviors, thus substantially improving the odds of successful recovery
from OUD, particularly when coupled with psychosocial interventions. This crisis has crystalized the need to
establish new pathways to develop additional and/or adjunctive therapeutics to extend recovery and improve
outcomes in this chronic medical disorder. However, the surprising lack of knowledge of the molecular, genetic,
and epigenetic neuropathophysiology of OUD has restricted our understanding and treatment of this disorder.
One such cellular adaptation involves altered gene expression in the absence of changes in gene encoding
through epigenetics. In this light, the intended biological target of the present U18 is a member of the
bromodomain and extra-terminal domain-containing (BET) family of chromatin “reader” proteins. The BET family
is comprised of bromodomain testis-specific protein (BRDT) and bromodomain (BRD)-containing protein 2
(BRD2), BRD3 and BRD4. Our preliminary data indicate that increased expression of BRD4 in the nucleus
accumbens (NAc) may be a driver of withdrawal-related sequela associated with continued oxycodone-taking.
We also found that the patent-protected, highly selective BDR4 inhibitor ZL0987 exerted a sustained suppression
of oxycodone self-administration. Based upon these findings, we will test the hypotheses that the highly selective
BRD4 inhibitor ZL0987 will suppress oxycodone, but not food, self-administration upon chronic administration
(Aim 1) and that pretreatment with ZL0987, which reduces oxycodone SA, will negate or normalize transcriptomic
profiles and BDR4 protein interactions relative to food self-administration. Target engagement will be
investigated through transcriptional and chromatin-related consequences of oxycodone vs. food self-
administration using genome-wide and candidate (i.e., BRD4)-based approaches [e.g., RNA-Seq and chromatin
immunoprecipitation with DNA sequencing (ChIP-Seq) analysis of BRD4 binding sites] in NAc harvested from
rats at early and late withdrawal from oxycodone or food self-administration under controlled conditions. The
results from the present studies will lay the foundation for a completely novel and highly relevant research track
that will foster in-depth investigation of differential BRD4 involvement in neurobiological circuitry involved in OUD.
This is a highly innovative and speculative direction and the outcomes will position our team to move forward
into initiatives that enable development of novel ligands that inhibit the BRD4 protein complex, identification of
potential off-target interactions for lead drug candidates, and in vivo studies to restore BRD4 protein function to
ameliorate OUD. These innovative aims are consi...

## Key facts

- **NIH application ID:** 10107610
- **Project number:** 1U18DA052546-01
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Noelle C Anastasio
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $237,000
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107610

## Citation

> US National Institutes of Health, RePORTER application 10107610, BRD4 Inhibition for Opioid Pharmacotherapy (1U18DA052546-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10107610. Licensed CC0.

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