Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma

被引：131

作者：

Konteatis, Zenon ^{[1
]}

Artin, Erin ^{[1
,7
]}

Nicolay, Brandon ^{[1
]}

Straley, Kimberly ^{[1
,8
]}

Padyana, Anil K. ^{[1
]}

Jin, Lei ^{[1
]}

Chen, Yue ^{[1
]}

Narayaraswamy, Rohini ^{[1
]}

Tong, Shuilong ^{[2
]}

Wang, Feng ^{[3
]}

Zhou, Ding ^{[4
,9
]}

Cui, Dawei ^{[4
,10
]}

Cai, Zhenwei ^{[4
]}

Luo, Zhiyong ^{[5
]}

Fang, Cheng ^{[5
]}

Tang, Huachun ^{[5
]}

Lv, Xiaobing ^{[5
,14
]}

Nagaraja, Raj ^{[1
]}

Yang, Hua ^{[1
]}

Su, Shin-San M. ^{[1
,12
]}

Sui, Zhihua ^{[1
]}

Dang, Lenny ^{[1
]}

Yen, Katharine ^{[1
,13
]}

Popovici-Muller, Janeta ^{[1
,12
]}

Codega, Paolo ^{[6
,11
]}

Campos, Carl ^{[6
]}

Mellinghoff, Ingo K. ^{[6
]}

Biller, Scott A. ^{[1
]}

机构：

[1] Agios Pharmaceut Inc, Cambridge, MA 02139 USA

[2] Viva Biotech, Shanghai 201203, Peoples R China

[3] Wuxi Biortus Biosci Co Ltd, Jiangyin 214437, Peoples R China

[4] PharmaResources, Shanghai 201201, Peoples R China

[5] ChemPartner, Shanghai 201203, Peoples R China

[6] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA

[7] KSQ Therapeut, Cambridge, MA 02139 USA

[8] Vertex Pharmaceut, Boston, MA 02210 USA

[9] Zion Pharma, Shanghai 200000, Peoples R China

[10] Suzhou Zelgen Biopharmaceut, Kunshan 215300, Peoples R China

[11] Sundia, Shanghai 201203, Peoples R China

[12] Decibel Therapeut, Cambridge, MA 02215 USA

[13] Auron Therapeut, Wellesley, MA 02481 USA

[14] Italfarmaco SpA, I-20092 Cinisello Balsamo, Italy

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2020年 / 11卷 / 02期

关键词：

Isocitrate dehydrogenase; mutant IDH1/mIDH2; AG-881; vorasidenib; 2-hydroxyglutarate; GENOMIC ANALYSIS; MUTATIONS;

D O I：

10.1021/acsmedchemlett.9b00509

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.

引用

页码：101 / 107

页数：13

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