5TQH

IDH1 R132H mutant in complex with IDH889

5TQH の概要

• エントリーDOI: 10.2210/pdb5tqh/pdb
• 分子名称: Isocitrate dehydrogenase [NADP] cytoplasmic, CITRATE ANION, (4S)-3-[2-({(1S)-1-[5-(4-fluoro-3-methylphenyl)pyrimidin-2-yl]ethyl}amino)pyrimidin-4-yl]-4-(propan-2-yl)-1,3-oxazolidin-2-one, ... (5 entities in total)
• 機能のキーワード: isocitrate dehydrogenase, rossmann fold, nadph, inhibitor, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : O75874
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 193133.58

構造登録者

Xie, X.,Kulathila, R. (登録日: 2016-10-24, 公開日: 2017-01-25, 最終更新日: 2024-03-06)

主引用文献

Levell, J.R.,Caferro, T.,Chenail, G.,Dix, I.,Dooley, J.,Firestone, B.,Fortin, P.D.,Giraldes, J.,Gould, T.,Growney, J.D.,Jones, M.D.,Kulathila, R.,Lin, F.,Liu, G.,Mueller, A.,van der Plas, S.,Slocum, K.,Smith, T.,Terranova, R.,Toure, B.B.,Tyagi, V.,Wagner, T.,Xie, X.,Xu, M.,Yang, F.S.,Zhou, L.X.,Pagliarini, R.,Cho, Y.S.
Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1.
ACS Med Chem Lett, 8:151-156, 2017

PubMed Abstract: High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1. Synthesis of the four separate stereoisomers identified the (,)-diastereomer (, ) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1. Initial structure-activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood-brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (,)-oxazolidinone () with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.

PubMed: 28197303
DOI: 10.1021/acsmedchemlett.6b00334

実験手法

X-RAY DIFFRACTION (2.2 Å)