# Discovering and Exploiting Selectivity within Tandem Bromodomains

> **NIH NIH R35** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $390,000

## Abstract

PROJECT SUMMARY
The goals of this research program are to understand how bromodomain ‘reading’ of the epigenetic histone
language is regulated by metabolism (Direction 1) and disease-associated missense variants (Direction 2). Our
approach is multidisciplinary, focusing on mechanisms and developing novel chemical tools as starting points
for drug development (Direction 3). Bromodomains bind acyl-lysines on histones and other nuclear proteins to
modulate transcription. The importance of bromodomain-mediated transcription in human disease is well-
established. Bromodomain inhibitors are in clinical trials for multiple indications, including cardiovascular
disease and cancer. Despite these achievements, several critical questions remain. For example, histone and
transcription factor lysine residues are modified by an array of non-acetyl acylations. These acylations are
derived from acyl-CoA metabolites, indicating an intricate interplay between the cellular energy states that
modulate acyl-CoA levels and bromodomain-mediated transcriptional regulation. Where, when, and how these
acylations recruit bromodomains to chromatin for transcriptional regulation is poorly understood. Therefore, we
are testing the hypothesis that changes in metabolic flux induce distinct histone acylations that are ‘read’ by
specific bromodomains to regulate transcription and inflammation (Direction 1). Bromodomains are also hot
spots for cancer-associated missense variants. However, the impacts of these variants on bromodomain-
mediated transcriptional regulation are largely unknown. Elucidating the mechanisms through which
bromodomain missense variants transcriptionally regulate key cancer signaling pathways will spur the
development of novel precision medicine therapeutic approaches. Accordingly, we are testing the hypothesis
that bromodomain missense variants with disrupted stability, structure, and dynamics attenuate bromodomain-
mediated transcriptional regulation of key cancer signaling pathways (Direction 2). Here, we employ the
integrated computational and biophysical pipeline that we developed in the Medical College of Wisconsin
Structural Genomics Unit to interrogate disease-associated missense variants from protein structure to
integrative transcriptomics. Another critical barrier to progress in bromodomain biology is the lack of inhibitors
and chemical probes specifically targeting individual bromodomains. We are overcoming this barrier by
developing selective bromodomain inhibitors using a novel fragment NMR screening pipeline we pioneered in
the Medical College of Wisconsin Program in Chemical Biology (Direction 3). In line with the NIGMS mission to
increase understanding of biological processes and advance knowledge of disease, our mechanistic inquiries
into bromodomain-mediated transcriptional regulation, coupled with our development of inhibitors and chemical
probes, will distinguish the differential activities of bromodomains in cell and animal models of he...

## Key facts

- **NIH application ID:** 10764853
- **Project number:** 2R35GM128840-06
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Brian Christopher Smith
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,000
- **Award type:** 2
- **Project period:** 2018-09-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764853

## Citation

> US National Institutes of Health, RePORTER application 10764853, Discovering and Exploiting Selectivity within Tandem Bromodomains (2R35GM128840-06). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10764853. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*