5KHM

The first BET bromodomain of BRD4 bound to compound 13 in a bivalent manner

5KHM の概要

• エントリーDOI: 10.2210/pdb5khm/pdb
• 分子名称: Bromodomain-containing protein 4, (3~{R})-4-[2-[4-[1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: bromodomain, transcription factor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: O60885
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30954.62

構造登録者

Patel, J. (登録日: 2016-06-15, 公開日: 2016-09-21, 最終更新日: 2023-09-27)

主引用文献

Bradbury, R.H.,Callis, R.,Carr, G.R.,Chen, H.,Clark, E.,Feron, L.,Glossop, S.,Graham, M.A.,Hattersley, M.,Jones, C.,Lamont, S.G.,Ouvry, G.,Patel, A.,Patel, J.,Rabow, A.A.,Roberts, C.A.,Stokes, S.,Stratton, N.,Walker, G.E.,Ward, L.,Whalley, D.,Whittaker, D.,Wrigley, G.,Waring, M.J.
Optimization of a Series of Bivalent Triazolopyridazine Based Bromodomain and Extraterminal Inhibitors: The Discovery of (3R)-4-[2-[4-[1-(3-Methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-piperidyl]phenoxy]ethyl]-1,3-dimethyl-piperazin-2-one (AZD5153).
J.Med.Chem., 59:7801-7817, 2016

PubMed Abstract: Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.

PubMed: 27528113
DOI: 10.1021/acs.jmedchem.6b00070

実験手法

X-RAY DIFFRACTION (1.48 Å)