Discovery, X‑ray
Crystallography, and Anti-inflammatory
Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors
Targeting a Distinct New Binding Site
Version 2 2022-01-06, 17:42Version 2 2022-01-06, 17:42
Version 1 2022-01-04, 21:15Version 1 2022-01-04, 21:15
journal contribution
posted on 2022-01-06, 17:42authored byZhiqing Liu, Yi Li, Haiying Chen, Hsien-Tsung Lai, Pingyuan Wang, Shwu-Yuan Wu, Eric A. Wold, Paul G. Leonard, Sarah Joseph, Haitao Hu, Cheng-Ming Chiang, Allan R. Brasier, Bing Tian, Jia Zhou
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 αB and αC
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.