8B5I

C-TERMINAL BROMODOMAIN OF HUMAN BRD2 WITH 7,8-dimethoxy-1,3-dimethyl-1,3-dihydro-2H-benzo[d]azepin-2-one

これはPDB形式変換不可エントリーです。

8B5I の概要

• エントリーDOI: 10.2210/pdb8b5i/pdb
• 関連するPDBエントリー: 8B5G 8B5H
• 分子名称: Bromodomain-containing protein 2, 1,2-ETHANEDIOL, 2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL, ... (5 entities in total)
• 機能のキーワード: inhibitor complex bromodomain, 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: 14282.46

構造登録者

Chung, C. (登録日: 2022-09-22, 公開日: 2022-11-30, 最終更新日: 2024-05-01)

主引用文献

Humphreys, P.G.,Anderson, N.A.,Bamborough, P.,Baxter, A.,Chung, C.W.,Cookson, R.,Craggs, P.D.,Dalton, T.,Fournier, J.C.L.,Gordon, L.J.,Gray, H.F.,Gray, M.W.,Gregory, R.,Hirst, D.J.,Jamieson, C.,Jones, K.L.,Kessedjian, H.,Lugo, D.,McGonagle, G.,Patel, V.K.,Patten, C.,Poole, D.L.,Prinjha, R.K.,Ramirez-Molina, C.,Rioja, I.,Seal, G.,Stafford, K.A.J.,Shah, R.R.,Tape, D.,Theodoulou, N.H.,Tomlinson, L.,Ukuser, S.,Wall, I.D.,Wellaway, N.,White, G.
Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432.
J.Med.Chem., 65:15174-15207, 2022

PubMed Abstract: The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 () as an oral candidate quality molecule.

PubMed: 36378954
DOI: 10.1021/acs.jmedchem.2c01102

実験手法

X-RAY DIFFRACTION (1.604 Å)