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

Cho, Young, Liu, Gang, Caferro, Thomas, Shafer, Cynthia, Manning, James, Sendzik, Martin, Shultz, Michael, Chenail, Gregg, Dooley, Julie, Farsidjani, Alireza, Chen, Jinyun, Kulathila, Raviraj, Xie, Xiaoling, Dodd, Stephanie, Gould, Ty, Liang, Guiqing, Heimbach, Tycho, Slocum, Kelly, Pu, Minying, Pagliarini, Raymond and Growney, Joseph (2017) Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor. ACS Medicinal Chemistry Letters, 8 (10). pp. 1116-1121. ISSN 19485875


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.

Item Type: Article
Keywords: brain penetration clinical candidate in vivo anticancer activity inhibition of 2-HG production Mutant IDH1
Date Deposited: 17 Jan 2018 00:45
Last Modified: 25 Jan 2019 00:45


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