6B0Z

IDH1 R132H mutant in complex with IDH305

Summary for 6B0Z

• Entry DOI: 10.2210/pdb6b0z/pdb
• Descriptor: Isocitrate dehydrogenase [NADP] cytoplasmic, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (4R)-4-[(1S)-1-fluoroethyl]-3-[2-({(1S)-1-[4-methyl-2'-(trifluoromethyl)[3,4'-bipyridin]-6-yl]ethyl}amino)pyrimidin-4-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: 194330.37

Authors

Xie, X.,Kulathila, R. (deposition date: 2017-09-15, release date: 2017-11-08, Last modification date: 2024-03-06)

Primary citation

Cho, Y.S.,Levell, J.R.,Liu, G.,Caferro, T.,Sutton, J.,Shafer, C.M.,Costales, A.,Manning, J.R.,Zhao, Q.,Sendzik, M.,Shultz, M.,Chenail, G.,Dooley, J.,Villalba, B.,Farsidjani, A.,Chen, J.,Kulathila, R.,Xie, X.,Dodd, S.,Gould, T.,Liang, G.,Heimbach, T.,Slocum, K.,Firestone, B.,Pu, M.,Pagliarini, R.,Growney, J.D.
Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor.
ACS Med Chem Lett, 8:1116-1121, 2017

PubMed Abstract: Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg. Having identified an allosteric, induced pocket of IDH1, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate (), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. () has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

PubMed: 29057061
DOI: 10.1021/acsmedchemlett.7b00342

Experimental method

X-RAY DIFFRACTION (2.334 Å)