8PX2

C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 1,3-dimethyl-5-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one

8PX2 の概要

• エントリーDOI: 10.2210/pdb8px2/pdb
• 分子名称: Bromodomain-containing protein 2, 1,3-dimethyl-5-[1-(oxan-4-ylmethyl)benzimidazol-2-yl]pyridin-2-one, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• 機能のキーワード: bromodomain inhibitor, complex, 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: 13965.11

構造登録者

Chung, C.W. (登録日: 2023-07-22, 公開日: 2023-10-18, 最終更新日: 2023-12-27)

主引用文献

Bradley, E.,Fusani, L.,Chung, C.W.,Craggs, P.D.,Demont, E.H.,Humphreys, P.G.,Mitchell, D.J.,Phillipou, A.,Rioja, I.,Shah, R.R.,Wellaway, C.R.,Prinjha, R.K.,Palmer, D.S.,Kerr, W.J.,Reid, M.,Wall, I.D.,Cookson, R.
Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe.
J.Med.Chem., 66:15728-15749, 2023

PubMed Abstract: Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

PubMed: 37967462
DOI: 10.1021/acs.jmedchem.3c00906

実験手法

X-RAY DIFFRACTION (1.622 Å)