Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation

Zhiqing Liu, Haiying Chen, Pingyuan Wang, Yi Li, Eric A. Wold, Paul G. Leonard, Sarah Joseph, Allan R. Brasier, Bing Tian, Jia Zhou

Research output: Contribution to journalArticle

Abstract

Bromodomain-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel chromone derivatives via scaffold hopping to discover a new class of orally bioavailable BRD4-selective inhibitors. Two potent BRD4 bromodomain 1 (BD1)-selective inhibitors 44 (ZL0513) and 45 (ZL0516) have been discovered with high binding affinity (IC50 values of 67-84 nM) and good selectivity over other BRD family proteins and distant BD-containing proteins. Both compounds significantly inhibited the expression of Toll-like receptor-induced inflammatory genes in vitro and airway inflammation in murine models. The cocrystal structure of 45 in complex with human BRD4 BD1 at a high resolution of 2.0 Å has been solved, offering a solid structural basis for its binding validation and further structure-based optimization. These BRD4 BD1 inhibitors demonstrated impressive in vivo efficacy and overall promising pharmacokinetic properties, indicating their therapeutic potential for the treatment of inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)5242-5256
Number of pages15
JournalJournal of medicinal chemistry
Volume63
Issue number10
DOIs
StatePublished - May 28 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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