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ACS Med Chem Lett. 2017 Sep 18;8(10):1116-1121. doi: 10.1021/acsmedchemlett.7b00342. eCollection 2017.

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

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  • 1Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

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.

KEYWORDS:

Mutant IDH1; brain penetration; clinical candidate; in vivo anticancer activity; inhibition of 2-HG production

PMID:
29057061
PMCID:
PMC5641959
[Available on 2018-10-12]
DOI:
10.1021/acsmedchemlett.7b00342
[PubMed]
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