8ZMQ

Crystal Structure of the second bromodomain of human BRD4 BD2 in complex with the inhibitor Y13190

This is a non-PDB format compatible entry.

Summary for 8ZMQ

• Entry DOI: 10.2210/pdb8zmq/pdb
• Descriptor: BRD4_HUMAN, 2-(2-(adamantan-1-yl)-4-ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: brd4, bd2, bromodomain, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 20
• Total formula weight: 355750.30

Authors

Li, J.,Hu, Q.,Xu, H.,Zhao, X.,Zhang, C.,Zhu, R.,Wu, X.,Zhang, Y.,Xu, Y. (deposition date: 2024-05-23, release date: 2024-12-11, Last modification date: 2024-12-25)

Primary citation

Li, J.,Hu, Q.,Zhu, R.,Dong, R.,Shen, H.,Hu, J.,Zhang, C.,Zhang, X.,Xu, T.,Xiang, Q.,Zhang, Y.,Lin, B.,Zhao, L.,Wu, X.,Xu, Y.
Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors.
J.Med.Chem., 67:21577-21616, 2024

PubMed Abstract: Pan-BD2 inhibitors have been shown to retain an antileukemia effect and display less dose-limiting toxicities than pan-BET inhibitors. However, it is necessary to consider the potential off-target toxicity associated with the inhibition of four BET BD2 proteins. To date, no BRD4 BD2 domain selective inhibitor has been reported. Based on our previous pan-BD2 inhibitor (XY153), we successfully identified (XY221) as the first BRD4 BD2-selective inhibitor. demonstrated potent binding affinity for BRD4 BD2 (IC = 5.8 nM), along with high pan-BD2 selectivity (667-fold over BRD4 BD1) and BRD4 BD2 domain selectivity (9-32-fold over BRD2/3/T BD2). The BRD4 BD2 selectivity of was further confirmed by the BLI assay, showing 66-144-fold selectivity over other BET BD2 domains. exhibited good liver microsomal stability ( > 120 min) and pharmacokinetic properties ( = 13.1%). These data indicate that may serve as a valuable candidate for BRD4 BD2 advancing epigenetic research.

PubMed: 39602227
DOI: 10.1021/acs.jmedchem.4c02516

Experimental method

X-RAY DIFFRACTION (2.2 Å)