8WYG

Crystal Structure of the second bromodomain of human BRD2 in complex with the inhibitor 22

Summary for 8WYG

• Entry DOI: 10.2210/pdb8wyg/pdb
• Descriptor: Bromodomain-containing protein 2, 2-[[5-[2-(4-fluoranyl-2,6-dimethyl-phenoxy)-5-(2-oxidanylpropan-2-yl)phenyl]-1-methyl-2-oxidanylidene-pyridin-4-yl]amino]-~{N}-(4-oxidanylcyclohexyl)ethanamide (3 entities in total)
• Functional Keywords: brd2(2), bromodomain, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 66131.47

Authors

Xu, H.,Zhao, X.,Shen, H.,Xu, Y.,Wu, X. (deposition date: 2023-10-30, release date: 2024-01-24, Last modification date: 2024-02-07)

Primary citation

Jiang, W.,Hou, Q.,Xu, H.,Yang, K.,Wang, X.,Zhang, K.,Zeng, Y.,Li, W.,Wang, B.,Luo, G.,Zhao, X.,Shen, H.,Xu, Y.,Wu, X.
Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.
J.Med.Chem., 67:1513-1532, 2024

PubMed Abstract: Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of -BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound (IC = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to (IC = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (: 2583-fold; : 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis . Excellent antitumor efficacy with was achieved in an MV;411 mouse xenograft model. Pleasingly, compound (hERG IC > 30 μM) mitigated the inhibition of the human ether-à-go-go-related gene (hERG) ion channel compared with (hERG IC = 2.8 μM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents.

PubMed: 38175809
DOI: 10.1021/acs.jmedchem.3c02104

Experimental method

X-RAY DIFFRACTION (3.13 Å)