Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site

Zhiqing Liu, Yi Li, Haiying Chen, Hsien Tsung Lai, Pingyuan Wang, Shwu Yuan Wu, Eric A. Wold, Paul G. Leonard, Sarah Joseph, Haitao Hu, Cheng Ming Chiang, Allan R. Brasier, Bing Tian, Jia Zhou

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and the progress toward clinical development of effective therapeutics. Here we report the discovery of a potent BRD4 bromodomain 1 (BD1)-selective inhibitor ZL0590 (52) targeting a unique, previously unreported binding site, while exhibiting significant anti-inflammatory activities in vitro and in vivo. The X-ray crystal structural analysis of ZL0590 in complex with human BRD4 BD1 and the associated mutagenesis study illustrate a first-in-class nonacetylated lysine (KAc) binding site located at the helix αB and αC interface that contains important BRD4 residues (e.g., Glu151) not commonly shared among other family members and is spatially distinct from the classic KAc recognition pocket. This new finding facilitates further elucidation of the complex biology underpinning bromodomain specificity among BRD4 and its protein-protein interaction partners.

Original languageEnglish (US)
Pages (from-to)2388-2408
Number of pages21
JournalJournal of Medicinal Chemistry
Volume65
Issue number3
DOIs
StatePublished - Feb 10 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

MD Anderson CCSG core facilities

  • NMR Facility

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