5TQH

IDH1 R132H mutant in complex with IDH889

Summary for 5TQH

• Entry DOI: 10.2210/pdb5tqh/pdb
• Descriptor: 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)
• Functional Keywords: isocitrate dehydrogenase, rossmann fold, nadph, inhibitor, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : O75874
• Total number of polymer chains: 4
• Total formula weight: 193133.58

Authors

Xie, X.,Kulathila, R. (deposition date: 2016-10-24, release date: 2017-01-25, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2 Å)