# BRD4 Inhibitor

> **NIH NIH U18** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $219,528

## Abstract

PROJECT SUMMARY
Methamphetamine (METH) use disorder is a rising public health crisis to which there are no available FDA-
approved therapeutics. METH is a highly addictive and neurotoxic substance that can trigger neuroinflammation
and induce long-lasting gene expression changes across the brain reward system. Indeed, epigenetic enzymes
have shown the ability to regulate both drug-induced transcriptional changes and the expression of inflammatory
cytokines. For instance, it has been shown that changes in histone acetylation can drive transcriptional and
neuroinflammatory responses to METH exposure. Interestingly, expression of the histone acetylation reader,
Brd4, and histone acetyltransferase, P300/CBP, increases following cocaine, alcohol and opioid exposure.
Further, pharmacological inhibition of these enzymes has been shown to curb drug-seeking in humans and
decrease neuroinflammation, altogether suggesting that Brd4 and P300/CBP may play important roles in
addiction pathophysiology. However, the potential role of Brd4 and P300/CBP in METH reinforcement and
related inflammatory signaling remains poorly understood. We therefore propose to study the role of Brd4 and
P300/CBP in METH reinforcement and METH-induced neuroinflammation by using a mouse model of METH
intravenous self-administration. We will inhibit Brd4 and P300/CBP with a novel small molecule inhibitor
(EP32010) that is brain-penetrant and highly selective for Brd4 and P300/CBP. We will test whether dual
inhibition of Brd4 and P300/CBP can curb METH-taking, relapse, as well as dampen neuroinflammatory
responses to the drug. Taken together, these studies will sharpen our understanding of the epigenetic
mechanisms underlying the reinforcing and neuroinflammatory properties of METH, and how these processes
can help shape the course of METH use disorder. More broadly, we hope results from these studies will pave
new avenues toward the development of effective cessation therapeutics.

## Key facts

- **NIH application ID:** 10107498
- **Project number:** 1U18DA052533-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Claes Robert Wahlestedt
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $219,528
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107498

## Citation

> US National Institutes of Health, RePORTER application 10107498, BRD4 Inhibitor (1U18DA052533-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10107498. Licensed CC0.

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