Bromodomain-containing protein 4 (BRD4): a key player in inflammatory bowel disease and potential to inspire epigenetic therapeutics

ABSTRACT

Introduction

Inflammatory bowel diseases (IBDs) are debilitating chronic inflammatory disorders with increasing prevalence worldwide. Epigenetic regulator bromodomain-containing protein 4 (BRD4) is critical in controlling gene expression of IBD-associated inflammatory cytokine networks. BRD4 as a promising therapeutic target is also tightly associated with many other diseases, such as airway inflammation and fibrosis, cancers, infectious diseases and central nervous system disorders.

Areas covered

This review briefly summarized the critical role of BRD4 in the pathogenesis of IBDs and the current clinical landscape of developing bromodomain and extra terminal domain (BET) inhibitors. The challenges and opportunities as well as future directions of targeting BRD4 inhibition for potential IBD medications were also discussed.

Expert opinion

Targeting BRD4 with potent and specific inhibitors may offer novel effective therapeutics for IBD patients, particularly those who are refractory to anti-TNFα therapy and IBD-related profibrotic. Developing highly specific BRD4 inhibitors for IBD medications may help erase the drawbacks of most current pan-BET/BRD4 inhibitors, such as off-target effects, poor oral bioavailability, and low gut mucosal absorbance. Novel strategies such as combinatorial therapy, BRD4-based dual inhibitors and proteolysis targeting chimeras (PROTACs) may also have great potential to mitigate side effects and overcome drug resistance during IBD treatment.

KEYWORDS:

• Bromodomain-containing protein 4 (BRD4)
• inflammatory bowel disease (IBD)
• ulcerative colitis (UC)
• Crohn’s disease (CD)
• epigenetics
• nuclear factor-κB (nfκb)
• drug target
• anti-inflammatory therapy

Article highlights

• Inflammatory bowel diseases (IBDs) are chronic intestinal disorders that severely threaten human health.

• Epigenetic regulator BRD4 is critical in controlling expression of IBD-associated inflammatory cytokine networks.

• The abundance of BRD4 activation marker H3K122Ac is significantly increased in human IBD (UC and CD) patient samples vs. healthy controls.

• Targeting BRD4 may offer a novel therapeutic strategy for treating IBD patients.

• Potent and specific BRD4 inhibitors may be helpful to avoid or mitigate the side effects of most pan-BET inhibitors.

• Novel strategies such as developing dual inhibitors and proteolysis targeting chimeras (PROTACs) may provide unique opportunities for targeting BRD4 towards epigenetic therapeutics against various human diseases, including IBD.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was partially supported by Crohn’s & Colitis Foundation Entrepreneurial Investing (EI) Initiative award (J Zhou and B Tian), Litwin IBD Pioneers Program Award (J Zhou and B Tian) from the Crohn’s & Colitis Foundation of America as well as the John D. Stobo, M.D. Distinguished Chair Endowment Fund (J Zhou).