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

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 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
URI:	https://oak.novartis.com/id/eprint/32520