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

被引：103

作者：

Cho, Young Shin ^{[1
]}

Levell, Julian R. ^{[1
,2
]}

Liu, Gang ^{[1
]}

Caferro, Thomas ^{[1
]}

Sutton, James ^{[1
,3
]}

Shafer, Cynthia M. ^{[1
]}

Costales, Abran ^{[1
]}

Manning, James R. ^{[1
]}

Zhao, Qian ^{[1
]}

Sendzik, Martin ^{[1
]}

Shultz, Michael ^{[1
]}

Chenail, Gregg ^{[1
]}

Dooley, Julia ^{[1
]}

Villalba, Brian ^{[1
]}

Farsidjani, Ali ^{[1
]}

Chen, Jinyun ^{[1
]}

Kulathila, Raviraj ^{[1
]}

Xie, Xiaoling ^{[1
]}

Dodd, Stephanie ^{[1
]}

Gould, Ty ^{[1
]}

Liang, Guiqing ^{[1
]}

Heimbach, Tycho ^{[1
]}

Slocum, Kelly ^{[1
]}

Firestone, Brant ^{[1
]}

Pu, Minying ^{[1
]}

Pagliarini, Raymond ^{[1
]}

Growney, Joseph D. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Constellat Pharmaceut, 215 First St,Suite 200, Cambridge, MA 02142 USA

[3] Ideaya Biosci, 280 Utah Ave,Suite 250, San Francisco, CA 94080 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 10期

关键词：

Mutant IDHI; inhibition of 2-HG production; in vivo anticancer activity; brain penetration; clinical candidate; ISOCITRATE DEHYDROGENASE 1; ACUTE MYELOID-LEUKEMIA; SELECTIVE-INHIBITION; SMALL-MOLECULE; MUTATIONS; OPPORTUNITIES; METABOLISM; HYPOXIA;

D O I：

10.1021/acsmedchemlett.7b00342

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Are). Having identified an allosteric, induced pocket of IDH1(R132H), 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 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.

引用

页码：1116 / 1121

页数：6

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