8WY3

Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 21

8WY3 の概要

• エントリーDOI: 10.2210/pdb8wy3/pdb
• 分子名称: Bromodomain-containing protein 4, ~{N}-cyclopropyl-2-[[5-[2-(4-fluoranyl-2,6-dimethyl-phenoxy)-5-(2-oxidanylpropan-2-yl)phenyl]-1-methyl-2-oxidanylidene-pyridin-4-yl]amino]ethanamide (3 entities in total)
• 機能のキーワード: brd4(1), bromodomain, protein binding
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 51782.69

構造登録者

Xu, H.,Zhao, X.,Shen, H.,Xu, Y.,Wu, X. (登録日: 2023-10-30, 公開日: 2024-01-24, 最終更新日: 2024-02-07)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.78 Å)