Enasidenib, Free Base

Soluble in DMSO. Enasidenib, also known as AG221, is a potent and selective IDH2 mutant enzyme inhibitor. It caused a significant decrease in R(-)-2-hydroxyglutarate in marrow, plasma, and urine and showed a dose-dependent survival benefit in a primary human AML xenograft model carrying the IDH2 R140Q mutation. Wang F., et al. 'AG-221 Offers a Survival Advantage In a Primary Human IDH2 Mutant AML Xenograft Model.' Blood 122: Abstract 240 (2013). Enasidenib is an orally available selective potent inhibitor of the mutant IDH2 enzyme. It inhibited 2HG production by the IDH2R140Q homodimer (IC50 = 100 nM), the IDH2R140Q/WT heterodimer (IC50 = 30 nM), and the IDH2R172K/WT heterodimer (IC50 = 10 nM), and inhibited the canonical forward (oxidative) reaction in the IDH2WT homodimer (IC50 = 1.8 µM). It inhibited 2HG production and promoted cellular differentiation in primary human IDH2 mutation-positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. It also provided significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. Yen K., et al. 'AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations.' Cancer Discov. 7: 478-493 (2017). Differentiation appears to be the main mechanism of enasidenib efficacy in relapsed/refractory AML patients. Amatangelo M.D., et al. 'Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response.' Blood 130: 732-741 (2017).