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

• Published in: Journal of medicinal chemistry Vol. 63; no. 10; pp. 5242 - 5256
• Main Authors: Liu, Zhiqing, Chen, Haiying, Wang, Pingyuan, Li, Yi, Wold, Eric A, Leonard, Paul G, Joseph, Sarah, Brasier, Allan R, Tian, Bing, Zhou, Jia
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28-05-2020; American Chemical Society (ACS)
• Subjects: Administration, Oral; Animals; Biological Availability; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Cell Line, Transformed; Chromones - administration & dosage; Chromones - chemistry; Chromones - pharmacology; Crystallization - methods; Crystallization - trends; Drug Discovery - methods; Drug Discovery - trends; Drug Evaluation, Preclinical - methods; Humans; Male; Mice; Mice, Inbred C57BL; Protein Structure, Secondary; Protein Structure, Tertiary; Structure-Activity Relationship; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c00035

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.