Konteatis Zenon, Artin Erin, Nicolay Brandon, Straley Kimberly, Padyana Anil K, Jin Lei, Chen Yue, Narayaraswamy Rohini, Tong Shuilong, Wang Feng, Zhou Ding, Cui Dawei, Cai Zhenwei, Luo Zhiyong, Fang Cheng, Tang Huachun, Lv Xiaobing, Nagaraja Raj, Yang Hua, Su Shin-San M, Sui Zhihua, Dang Lenny, Yen Katharine, Popovici-Muller Janeta, Codega Paolo, Campos Carl, Mellinghoff Ingo K, Biller Scott A
Agios Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, United States.
Viva Biotech, Shanghai 201203, China.
ACS Med Chem Lett. 2020 Jan 22;11(2):101-107. doi: 10.1021/acsmedchemlett.9b00509. eCollection 2020 Feb 13.
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.
突变型异柠檬酸脱氢酶（mIDH）1和2癌症相关酶的抑制剂可阻止致癌代谢物d-2-羟基戊二酸（2-HG）的积累，目前正处于临床研究阶段，用于治疗几种携带IDH突变的癌症。在此，我们描述了伏立西尼（AG-881）的发现，它是一种强效、口服、可穿透血脑屏障的mIDH1和mIDH2双重抑制剂。X射线共晶体结构使我们能够表征该化合物的结合位点，从而了解双重突变抑制作用。此外，伏立西尼可穿透多种临床前物种的大脑，并在原位胶质瘤小鼠模型中使胶质瘤组织中的2-HG生成抑制>97%。伏立西尼是一种新型的mIDH1/2双重抑制剂，目前正处于临床开发阶段，用于治疗低级别mIDH胶质瘤。
