7WKY

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor Y13153

Summary for 7WKY

• Entry DOI: 10.2210/pdb7wky/pdb
• Descriptor: Bromodomain-containing protein 4, 2-(2-cyclopentyl-1~{H}-imidazol-5-yl)-7-[2-(4-fluoranyl-2,6-dimethyl-phenoxy)-5-(2-oxidanylpropan-2-yl)phenyl]-5-methyl-furo[3,2-c]pyridin-4-one, GLYCEROL, ... (4 entities in total)
• Functional Keywords: brd4, bromodomain, inhibitor, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 52521.46

Authors

Li, J.,Zhang, C.,Xu, H.,Zhuang, X.,Wu, X.,Zhang, Y.,Xu, Y. (deposition date: 2022-01-12, release date: 2022-08-10, Last modification date: 2023-11-29)

Primary citation

Li, J.,Zhang, C.,Xu, H.,Wang, C.,Dong, R.,Shen, H.,Zhuang, X.,Chen, X.,Li, Q.,Lu, J.,Zhang, M.,Wu, X.,Loomes, K.M.,Zhou, Y.,Zhang, Y.,Liu, J.,Xu, Y.
Structure-Based Discovery and Optimization of Furo[3,2- c ]pyridin-4(5 H )-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.
J.Med.Chem., 65:5760-5799, 2022

PubMed Abstract: Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-]pyridin-4(5)-one derivatives as novel BD2-selective BET inhibitors. The representative compound (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. also demonstrated good metabolic stability in vitro. These data indicate that may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML).

PubMed: 35333526
DOI: 10.1021/acs.jmedchem.2c00100

Experimental method

X-RAY DIFFRACTION (2.83 Å)