JOURNAL ARTICLE

Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor

Young Shin Cho, Julian R Levell, Gang Liu, Thomas Caferro, James Sutton, Cynthia M Shafer, Abran Costales, James R Manning, Qian Zhao, Martin Sendzik, Michael Shultz, Gregg Chenail, Julia Dooley, Brian Villalba, Ali Farsidjani, Jinyun Chen, Raviraj Kulathila, Xiaoling Xie, Stephanie Dodd, Ty Gould, Guiqing Liang, Tycho Heimbach, Kelly Slocum, Brant Firestone, Minying Pu, Raymond Pagliarini, Joseph D Growney
ACS Medicinal Chemistry Letters 2017 October 12, 8 (10): 1116-1121
29057061
Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg132 . Having identified an allosteric, induced pocket of IDH1R132H , we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 ( 13 ), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 ( 13 ) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

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