Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma
Zenon Konteatis, Erin Artin, Brandon Nicolay, Kimberly Straley, Anil K. Padyana, Lei Jin, Yue Chen, Rohini Narayaraswamy, Shuilong Tong, Feng Wang, Ding Zhou, Dawei Cui, Zhen‐Wei Cai, Zhiyong Luo, Cheng Fang, Huachun Tang, Xiaobing Lv, Raj Nagaraja, Hua Yang, Shinsan M. Su, Zhihua Sui, Lenny Dang, Katharine Yen, Janeta Popovici-Müller, Paolo Codega, Carl Campos, Ingo K. Mellinghoff, Scott A. Biller
Abstract
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.