Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation
- 28 May 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (10), 5242-5256
- https://doi.org/10.1021/acs.jmedchem.0c00035
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 angstrom 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.Funding Information
- National Center for Advancing Translational Sciences (UL1TR001439)
- Sanofi
- National Institute of Allergy and Infectious Diseases (AI062885)
- University of Texas Medical Branch
- Crohn?s and Colitis Foundation
This publication has 38 references indexed in Scilit:
- Bromodomains: a new target class for drug developmentNature Reviews Drug Discovery, 2019
- Pharmacoproteomics reveal novel protective activity of bromodomain containing 4 inhibitors on vascular homeostasis in TLR3-mediated airway remodelingJournal of Proteomics, 2019
- Clinical epigenetics: seizing opportunities for translationNature Reviews Genetics, 2018
- Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodelingJournal of Allergy and Clinical Immunology, 2018
- Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammationEuropean Journal of Medicinal Chemistry, 2018
- Drug Discovery Targeting Bromodomain-Containing Protein 4Journal of Medicinal Chemistry, 2017
- Targeting bromodomains: epigenetic readers of lysine acetylationNature Reviews Drug Discovery, 2014
- BET domain co-regulators in obesity, inflammation and cancerNature Reviews Cancer, 2012
- Epigenome-wide association studies for common human diseasesNature Reviews Genetics, 2011
- Roles of histone acetyltransferases and deacetylases in gene regulationBioEssays, 1998