期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 3, 页码 2388-2408出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01851
关键词
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资金
- Crohn's & Colitis Foundation of America
- UTMB Technology Commercialization Program
- Sanofi Innovation Awards (iAwards)
- John D. Stobo, M.D. Distinguished Chair Endowment Fund
- NIH [AI157852, AI062885, CA251698]
- CPRIT [RP180349, RP190077]
- UT system proteomics network
- Crohn's & Colitis Foundation Entrepreneurial Investing (EI) Initiative award
- Litwin IBD Pioneers Program Award
A potent BRD4 BD1-selective inhibitor ZL0590 has been discovered, targeting a unique binding site and exhibiting significant anti-inflammatory activities. This finding provides new insights into the complex biology of bromodomain specificity among BRD4 and its protein-protein interaction partners.
Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and the progress toward clinical development of effective therapeutics. Here we report the discovery of a potent BRD4 bromodomain 1 (BD1)-selective inhibitor ZL0590 (52) targeting a unique, previously unreported binding site, while exhibiting significant anti-inflammatory activities in vitro and in vivo. The X-ray crystal structural analysis of ZL0590 in complex with human BRD4 BD1 and the associated mutagenesis study illustrate a first-in-class nonacetylated lysine (KAc) binding site located at the helix alpha B and alpha C interface that contains important BRD4 residues (e.g., Glu151) not commonly shared among other family members and is spatially distinct from the classic KAc recognition pocket. This new finding facilitates further elucidation of the complex biology underpinning bromodomain specificity among BRD4 and its protein-protein interaction partners.
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