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

Autor: Liu Z; Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States., Chen H; Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States., Wang P; Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States., Li Y; Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States., Wold EA; Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States., Leonard PG; Core for Biomolecular Structure and Function, MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States., Joseph S; Core for Biomolecular Structure and Function, MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States., Brasier AR; Institute for Clinical and Translational Research (ICTR), University of Wisconsin-Madison School of Medicine and Public Health, 4248 Health Sciences Learning Center, Madison, Wisconsin 53705, United States., Tian B; Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555, United States.; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555, United States., Zhou J; Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States.; Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555, United States.; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas 77555, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2020 May 28; Vol. 63 (10), pp. 5242-5256. Date of Electronic Publication: 2020 Apr 22.
DOI: 10.1021/acs.jmedchem.0c00035
Abstrakt: 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 (IC 50 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.
Databáze: MEDLINE
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