Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers

作者：Janeta Popovici-Müller, René M. Lemieux, Erin Artin, Jeffrey O. Saunders, Francesco G. Salituro, Jeremy Travins, Giovanni Cianchetta, Zhen‐Wei Cai, Ding Zhou, Dawei Cui, Ping Chen, Kimberly Straley, Erica R. Tobin, Fang Wang, Muriel D. David, Virginie Penard‐Lacronique, Cyril Quivoron, Véronique Saada, Stéphane de Botton, Stefan Größ, Lenny Dang, Hua Yang, Luke Utley, Yue Chen, Hyeryun Kim, Shengfang Jin, Zhiwei Gu, Yao Gui, Zhiyong Luo, Xiaobing Lv, Cheng Fang, Liping Yan, Andrew Olaharski, Lee Silverman, Scott A. Biller, Shinsan M. Su, Katharine Yen · 发表于：ACS Medicinal Chemistry Letters · 年份：2018 · DOI：10.1021/acsmedchemlett.7b00421 · 被引用次数：453 · 研究领域：Cancer, Hypoxia, and Metabolism、Glioma Diagnosis and Treatment、Histone Deacetylase Inhibitors Research

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.