Dataset Information

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 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.

SUBMITTER: Cho YS

PROVIDER: S-EPMC5641959 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Cho Young Shin YS Levell Julian R JR Liu Gang G Caferro Thomas T Sutton James J Shafer Cynthia M CM Costales Abran A Manning James R JR Zhao Qian Q Sendzik Martin M Shultz Michael M Chenail Gregg G Dooley Julia J Villalba Brian B Farsidjani Ali A Chen Jinyun J Kulathila Raviraj R Xie Xiaoling X Dodd Stephanie S Gould Ty T Liang Guiqing G Heimbach Tycho T Slocum Kelly K Firestone Brant B Pu Minying M Pagliarini Raymond R Growney Joseph D JD

ACS medicinal chemistry letters 20170918 10

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 po ...[more]

PMID: 29057061

Dataset Information

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

Publications

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

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