7OER

C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH N-(2,2-diphenylethyl)-1,5-dimethyl-N-(2-(methylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide

これはPDB形式変換不可エントリーです。

7OER の概要

• エントリーDOI: 10.2210/pdb7oer/pdb
• 関連するPDBエントリー: 7OE0 7OEP
• 分子名称: Bromodomain-containing protein 2, N-(2,2-diphenylethyl)-1,5-dimethyl-N-[2-(methylamino)-2-oxidanylidene-ethyl]-6-oxidanylidene-pyridine-3-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: inhibitor, histone, epigenetic reader, bromodomain, brd2, bromodomain containing protein 2, antagonist, nuclear protein
• 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: 13912.03

構造登録者

Chung, C. (登録日: 2021-05-03, 公開日: 2021-07-21, 最終更新日: 2024-05-01)

主引用文献

Rianjongdee, F.,Atkinson, S.J.,Chung, C.W.,Grandi, P.,Gray, J.R.J.,Kaushansky, L.J.,Medeiros, P.,Messenger, C.,Phillipou, A.,Preston, A.,Prinjha, R.K.,Rioja, I.,Satz, A.L.,Taylor, S.,Wall, I.D.,Watson, R.J.,Yao, G.,Demont, E.H.
Discovery of a Highly Selective BET BD2 Inhibitor from a DNA-Encoded Library Technology Screening Hit.
J.Med.Chem., 64:10806-10833, 2021

PubMed Abstract: Second-generation bromodomain and extra terminal (BET) inhibitors, which selectively target one of the two bromodomains in the BET proteins, have begun to emerge in the literature. These inhibitors aim to help determine the roles and functions of each domain and assess whether they can demonstrate an improved safety profile in clinical settings compared to pan-BET inhibitors. Herein, we describe the discovery of a novel BET BD2-selective chemotype using a structure-based drug design from a hit identified by DNA-encoded library technologies, showing a structural differentiation from key previously reported greater than 100-fold BD2-selective chemotypes GSK620, GSK046, and ABBV-744. Following a structure-based hypothesis for the selectivity and optimization of the physicochemical properties of the series, we identified (GSK040), an in vitro ready and in vivo capable BET BD2-inhibitor of unprecedented selectivity (5000-fold) against BET BD1, excellent selectivity against other bromodomains, and good physicochemical properties. This novel chemical probe can be added to the toolbox used in the advancement of epigenetics research.

PubMed: 34251219
DOI: 10.1021/acs.jmedchem.1c00412

実験手法

X-RAY DIFFRACTION (1.602 Å)