Janeta Popovici-Muller, R. Lemieux, Erin Artin, J. Saunders, F. Salituro, J. Travins, Giovanni Cianchetta, Z. Cai, Ding Zhou, D. Cui, Ping Chen, K. Straley, E. Tobin, F. Wang, M. David, V. Penard-Lacronique, C. Quivoron, V. Saada, S. de Botton, S. Gross, L. Dang, Hua Yang, L. Utley, Yue Chen, HyeRyun Kim, Shengfang Jin, Zhiwei Gu, Gui Yao, Zhiyong Luo, Xiaobing Lv, Cheng Fang, Liping Yan, A. Olaharski, L. Silverman, S. Biller, Shinsan M. Su, K. Yen
2018.1.19ACS Medicinal Chemistry Letters
tlooto Summary
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 is reported.
Abstract
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.
Citation format
POPOVICI-MULLER, Janeta, et al. Discovery of AG-120 (ivosidenib): A first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Medicinal Chemistry Letters, 2018, 9: 300–305.