6CZU

BRD4(BD1) complexed with 3219

6CZU の概要

• エントリーDOI: 10.2210/pdb6czu/pdb
• 分子名称: Bromodomain-containing protein 4, 5-(3,5-dimethyl-1,2-oxazol-4-yl)-1-({4-[(1R)-1-hydroxyethyl]phenyl}methyl)pyridin-2(1H)-one, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: bromodomain, brd4, 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: 16166.58

構造登録者

Lakshminarasimhan, D.,White, A.,Suto, R.K. (登録日: 2018-04-09, 公開日: 2018-09-26, 最終更新日: 2024-11-06)

主引用文献

Kharenko, O.A.,Patel, R.G.,Brown, S.D.,Calosing, C.,White, A.,Lakshminarasimhan, D.,Suto, R.K.,Duffy, B.C.,Kitchen, D.B.,McLure, K.G.,Hansen, H.C.,van der Horst, E.H.,Young, P.R.
Design and Characterization of Novel Covalent Bromodomain and Extra-Terminal Domain (BET) Inhibitors Targeting a Methionine.
J. Med. Chem., 61:8202-8211, 2018

PubMed Abstract: BET proteins are key epigenetic regulators that regulate transcription through binding to acetylated lysine (AcLys) residues of histones and transcription factors through bromodomains (BDs). The disruption of this interaction with small molecule bromodomain inhibitors is a promising approach to treat various diseases including cancer, autoimmune and cardiovascular diseases. Covalent inhibitors can potentially offer a more durable target inhibition leading to improved in vivo pharmacology. Here we describe the design of covalent inhibitors of BRD4(BD1) that target a methionine in the binding pocket by attaching an epoxide warhead to a suitably oriented noncovalent inhibitor. Using thermal denaturation, MALDI-TOF mass spectrometry, and an X-ray crystal structure, we demonstrate that these inhibitors selectively form a covalent bond with Met149 in BRD4(BD1) but not other bromodomains and provide durable transcriptional and antiproliferative activity in cell based assays. Covalent targeting of methionine offers a novel approach to drug discovery for BET proteins and other targets.

PubMed: 30165024
DOI: 10.1021/acs.jmedchem.8b00666

実験手法

X-RAY DIFFRACTION (1.47 Å)