期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 10, 页码 5242-5256出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00035
关键词
-
资金
- NIH [NIAID AI062885, UL1TR001439]
- UTMB Technology Commercialization Program
- Sanofi Innovation Awards (iAwards)
- John D. Stobo, M.D. Distinguished Chair Endowment Fund
- Crohn's & Colitis Foundation Entrepreneurial Investing (EI) Initiative award
- Crohn's & Colitis Foundation of America
- UT system proteomics network
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据