6ZB2

C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH GSK549

これはPDB形式変換不可エントリーです。

6ZB2 の概要

• エントリーDOI: 10.2210/pdb6zb2/pdb
• 分子名称: Bromodomain-containing protein 2, 1,2-ETHANEDIOL, ~{N}5-cyclopropyl-1-(1~{H}-indol-4-ylmethyl)-~{N}3-methyl-2-oxidanylidene-pyridine-3,5-dicarboxamide, ... (5 entities in total)
• 機能のキーワード: inhibitor, histone, epigenetic reader, bromodomain, brd2, bromodomain containing protein 2, antagonist, transcription
• 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: 14089.18

構造登録者

Chung, C. (登録日: 2020-06-06, 公開日: 2020-08-05, 最終更新日: 2024-05-01)

主引用文献

Seal, J.T.,Atkinson, S.J.,Aylott, H.,Bamborough, P.,Chung, C.W.,Copley, R.C.B.,Gordon, L.,Grandi, P.,Gray, J.R.J.,Harrison, L.A.,Hayhow, T.G.,Lindon, M.,Messenger, C.,Michon, A.M.,Mitchell, D.,Preston, A.,Prinjha, R.K.,Rioja, I.,Taylor, S.,Wall, I.D.,Watson, R.J.,Woolven, J.M.,Demont, E.H.
The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.
J.Med.Chem., 63:9093-9126, 2020

PubMed Abstract: The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, (GSK620) and (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.

PubMed: 32702236
DOI: 10.1021/acs.jmedchem.0c00796

実験手法

X-RAY DIFFRACTION (2.282 Å)