Enasidenib

An orally available, selective, potent inhibitor of mutant IDH2 with IC50s of 100-400 nM for IDH2R140Q homodimer, IDH2R172K homodimer and IDH2WT/R140Q, IDH2WT/R172K; less potent for IDH2WT homodimer and IDH1WT homodimer; suppresses 2HG production and induces cellular differentiation in primary human IDH2 mutation-positive AML cells ex vivo and in xenograft mouse models.Blood Cancer Approved (In Vitro) :Enasidenib (AG-221) reverses the effects of mutant IDH2 on DNA methylation in mutant stem/progenitor cells. Enasidenib induces differentiation and impairs self-renewal of IDH2-mutant leukemia cells, effects that are further enhanced by simultaneous inhibition of Flt3ITD. Enasidenib (AG-221) therapy induces differentiation of leukemic cells, with an increase in the CD11b+ population and a decrease in the c-Kit+ population in the peripheral blood at 2wks. (In Vivo) :Treatment with Enasidenib (AG-221) significantly improves survival in an IDH2-mutant acute myeloid leukemia (AML) primary xenograft mouse model. Enasidenib (AG-221), a mutant IDH2 inhibitor, remodels the epigenetic state of IDH2-mutant cells and induces alterations in self-renewal/differentiation in IDH2-mutant AML model in vivo. Enasidenib treatment (10mg/kg or 100mg/kg bid) leads to a reduction in 2-HG in vivo (96.7% below pre-treatment levels) . Moreover, Enasidenib treatment restores megakaryocyte-erythroid progenitor (MEP) differentiation that is suppressed by mutant IDH2 expression (mean MEP% mean, 39% Veh vs 50% AG-221) . Enasidenib therapy reverses the effects of mutant IDH2; a significant reduction is observed in DNA methylation, including 180 genes that have 20 or more hypomethylated differentially methylated cytosines (DMCs) following treatment. Enasidenib (100mg/kg bid) treatment of mice engrafted with Mx1-Cre IDH2R140QFlt3ITD AML cells markedly reduces 2-hydroxyglutarate (2-HG) levels consistent with on target inhibition. Enasidenib inhibits mutant IDH2-mediated 2-HG production.