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Letter
Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor Young Shin Cho, Julian Levell, Gang Liu, Thomas Caferro, James Sutton, Cynthia M. Shafer, Abran Costales, James R Manning, Qian Zhao, Martin Sendzik, Michael David Shultz, Gregg Chenail, Julia Dooley, Brian Villalba, Ali Farsidjani, Jinyun Chen, Raviraj Kulathila, Xiaoling Xie, Stephanie Dodd, Ty Gould, Guiqing Liang, Tycho Heimbach, Kelly Slocum, Brant Firestone, Minying Pu, Raymond Pagliarini, and Joseph D. Growney ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00342 • Publication Date (Web): 18 Sep 2017 Downloaded from http://pubs.acs.org on September 18, 2017
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Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor Young Shin Cho,* Julian R. Levell, Gang Liu, Thomas Caferro, James Sutton, Cynthia M. Shafer, Abran Costales, James R. Manning, Qian Zhao, Martin Sendzik, Michael Shultz, Gregg Chenail, Julia Dooley, Brian Villalba, Ali Farsidjani, Jinyun Chen, Raviraj Kulathila, Xiaoling Xie, Stephanie Dodd, Ty Gould, Guiqing Liang, Tycho Heimbach, Kelly Slocum, Brant Firestone, Minying Pu, Raymond Pagliarini and Joseph D. Growney* Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139 KEYWORDS mutant IDH1, inhibition of 2-HG production, in vivo anticancer activity, brain penetration, clinical candidate 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 3pyrimidin-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 towards the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor which 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.
Isocitrate dehydrogenase 1 (IDH1) is a NADP+, metal dependent oxidoreductase active in cellular metabolism.1-5 Wild-type IDH1 catalyzes the oxidative decarboxylation of isocitrate to give α-ketoglutarate (α-KG), while NADP+ is converted to NADPH. Heterozygous mutations in IDH1 at Arg132 have been tightly linked to various cancers including glioma, glioblastoma, AML, chondrosarcoma, and cholangiocarcinoma.6-9 This gain-of-function mutation reduces α-KG to R-2-hydroxyglutarate (2-HG) resulting in significantly elevated levels of this metabolite.10 Recently, both preclinical11-17 and clinical18-19 inhibition of mutant IDH1 have shown efficacy in various cancers, potentially offering a new treatment option to many patients with IDH1 mutation. Previously, we have reported hit-to-lead optimization efforts to identify a mutant specific inhibitor of IDH1.20 Compound 1 (IDH889) was shown to bind to an allosteric, induced-fit pocket of IDH1R132H with potent inhibition of 2-HG production as well as selectivity over the wildtype protein. Oral dosing of 1 in a mouse xenograft model demonstrated robust in vivo reduction of 2-HG tumor tissue levels in engineered HCT116 colon carcinoma cells expressing mutant IDH1R132H. While 1 is a potent and selective inhibitor that modulates 2-HG in xenograft models, it showed relatively high in vitro intrinsic clearance (Clint) across different species (rat/mouse/dog/human Clint 588/143/548/205 µl min-1 mg-1), high plasma protein binding (rat/mouse/human plasma protein binding
97/98/98%), and poor solubility (39 µM at pH 6.8) which we anticipated to entail very high human efficacious dose (>10 g BID). These considerable challenges to clinical development required additional optimization to identify a viable clinical candidate. Efforts focused on maintaining mutant IDH1 potency while optimizing the overall in vitro profile and subsequent translation to in vivo activity. The high unmet medical needs for glioma and glioblastoma patients justified additional selection criteria to identify inhibitors with potentially efficacious brain exposure. Initial modifications were focused on the amine sidechain. It was rationalized that increased polarity may reduce the brain penetration observed with 1,20 whereas reduction of the polarity would increase the lipophilicity, resulting in increased clearance and higher predicted dose for efficacy. Concomitant maintenance of the optimized biaryl system of 120 necessitated either retaining 2 nitrogens in the first aryl ring and none in the second, or transposing one nitrogen from the pyrimidine ring to the second ring to give a bipyridyl moiety. Pyrazine 2 was identified as a tolerated replacement for the 2,5pyrimidine ring, but this did not attenuate the high Clint or improve the solubility (
