6UWU

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor ZL0516

Summary for 6UWU

• Entry DOI: 10.2210/pdb6uwu/pdb
• Descriptor: Bromodomain-containing protein 4, 1,2-ETHANEDIOL, 2-{4-[(2R)-2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-3,5-dimethylphenyl}-5,7-dimethoxy-4H-1-benzopyran-4-one, ... (4 entities in total)
• Functional Keywords: bromodomain, inhibitor, complex, gene regulation, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15892.29

Authors

Leonard, P.G.,Joseph, S. (deposition date: 2019-11-05, release date: 2020-04-15, Last modification date: 2023-10-11)

Primary citation

Liu, Z.,Chen, H.,Wang, P.,Li, Y.,Wold, E.A.,Leonard, P.G.,Joseph, S.,Brasier, A.R.,Tian, B.,Zhou, J.
Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation.
J.Med.Chem., 63:5242-5256, 2020

PubMed 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 (ZL0513) and (ZL0516) have been discovered with high binding affinity (IC 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 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.

PubMed: 32255647
DOI: 10.1021/acs.jmedchem.0c00035

Experimental method

X-RAY DIFFRACTION (2 Å)