2. Academic Validation
  3. Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor

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

  • ACS Med Chem Lett. 2017 Sep 18;8(10):1116-1121. doi: 10.1021/acsmedchemlett.7b00342.
Young Shin Cho 1,  Julian R Levell 1,  Gang Liu 1,  Thomas Caferro 1,  James Sutton 1,  Cynthia M Shafer 1,  Abran Costales 1,  James R Manning 1,  Qian Zhao 1,  Martin Sendzik 1,  Michael Shultz 1,  Gregg Chenail 1,  Julia Dooley 1,  Brian Villalba 1,  Ali Farsidjani 1,  Jinyun Chen 1,  Raviraj Kulathila 1,  Xiaoling Xie 1,  Stephanie Dodd 1,  Ty Gould 1,  Guiqing Liang 1,  Tycho Heimbach 1,  Kelly Slocum 1,  Brant Firestone 1,  Minying Pu 1,  Raymond Pagliarini 1,  Joseph D Growney 1
Affiliations

Affiliation

  • 1 Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
PMID: 29057061 DOI: 10.1021/acsmedchemlett.7b00342
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.

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