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

Abstract

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 IDH1^R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for <i>in vivo</i> modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate <b>IDH305</b> (<b>13</b>), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited <i>in vivo</i> correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. <b>IDH305</b> (<b>13</b>) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.