Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

Pan Tang, Jifa Zhang, Jie Liu, Cheng Ming Chiang, Liang Ouyang

Research output: Contribution to journalReview articlepeer-review

Abstract

Bromodomain and extraterminal (BET) proteins bind acetylated lysine residues in histones and nonhistone proteins via tandem bromodomains and regulate chromatin dynamics, cellular processes, and disease procession. Thus targeting BET proteins is a promising strategy for treating various diseases, especially malignant tumors and chronic inflammation. Many pan-BET small-molecule inhibitors have been described, and some of them are in clinical evaluation. Nevertheless, the limited clinical efficacy of the current BET inhibitors is also evident and has inspired the development of new technologies to improve their clinical outcomes and minimize unwanted side effects. In this Review, we summarize the latest protein characteristics and biological functions of BRD4 as an example of BET proteins, analyze the clinical development status and preclinical resistance mechanisms, and discuss recent advances in BRD4-selective inhibitors, dual-target BET inhibitors, proteolysis targeting chimera degraders, and protein-protein interaction inhibitors.

Original languageEnglish (US)
Pages (from-to)2419-2435
Number of pages17
JournalJournal of Medicinal Chemistry
Volume64
Issue number5
DOIs
StatePublished - Mar 11 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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