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
  • 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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