5YOV

Crystal structure of BRD4-BD1 bound with hjp126

5YOV の概要

• エントリーDOI: 10.2210/pdb5yov/pdb
• 分子名称: Bromodomain-containing protein 4, (3~{R})-4-cyclopentyl-~{N}-(2,4-dimethylphenyl)-1,3-dimethyl-2-oxidanylidene-3~{H}-quinoxaline-6-carboxamide (3 entities in total)
• 機能のキーワード: bromodomain, transcription-inhibitor complex, transcription/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15490.89

構造登録者

Xiong, B.,Hu, J.,Li, Y.,Cao, D. (登録日: 2017-10-31, 公開日: 2018-11-07, 最終更新日: 2024-03-27)

主引用文献

Hu, J.,Wang, Y.,Li, Y.,Cao, D.,Xu, L.,Song, S.,Damaneh, M.S.,Li, J.,Chen, Y.,Wang, X.,Chen, L.,Shen, J.,Miao, Z.,Xiong, B.
Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups.
Eur.J.Med.Chem., 150:156-175, 2018

PubMed Abstract: Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1H)-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1H)-ones containing indoline group showed profound activities in molecular and cellular based assays. Throughout the study, compounds 9, 28 and 37 showed significant inhibitory activity for c-Myc or PD-L1 protein expression and mRNA transcription both at concentration of 0.2 and 1 μM. Compound 9 was found possessing the best balance of binding affinity, in vitro metabolic stability and in vivo pharmacokinetic properties. Therefore, it was selected for in vivo pharmacological study. By using MM.1S cell derived xenograft model, we confirmed compound 9 showed comparable in vivo tumor inhibition to phase II investigation drug I-BET762, which, together with the novel WPF binder, further indicated the utility of this series of BRD4 inhibitors.

PubMed: 29525435
DOI: 10.1016/j.ejmech.2018.02.070

実験手法

X-RAY DIFFRACTION (1.451 Å)