Enasidenib mesylate (AG-221 mesylate) is a potent and selective IDH2 mutase inhibitor that promotes differentiation of leukemia myeloid cells for the treatment of acute myeloid leukemia.

Reversing the effects of mutant IDH2 on DNA methylation in mutant stem/progenitor cells, Enasidenib mesylate (AG-221) induces differentiation and impairs self-renewal of IDH2-mutant leukemia cells. Simultaneous inhibition of Flt3ITD further enhances these effects. In the context of Enasidenib mesylate (AG-221) therapy, leukemic cells undergo differentiation, resulting in an increased CD11b+ population and a decreased c-Kit+ population in the peripheral blood at 2 weeks[2].

In an IDH2-mutant acute myeloid leukemia (AML) primary xenograft mouse model, treatment with Enasidenib mesylate (AG-221) significantly improves survival[1]. Acting as a mutant IDH2 inhibitor, enasidenib remodels the epigenetic state of IDH2-mutant cells, inducing alterations in self-renewal/differentiation in an IDH2-mutant AML model in vivo. Enasidenib mesylate treatment at doses of 10 mg/kg or 100 mg/kg bid results in a substantial reduction in 2-HG levels in vivo, reaching 96.7% below pre-treatment levels.Furthermore, Enasidenib mesylate treatment restores megakaryocyte-erythroid progenitor (MEP) differentiation, which is suppressed by mutant IDH2 expression, as indicated by a mean MEP% increase from 39% in the vehicle group to 50% in the AG-221 group. The therapy also reverses the effects of mutant IDH2 on DNA methylation, with a significant reduction observed in DNA methylation, affecting 180 genes with 20 or more hypomethylated differentially methylated cytosines (DMCs) following treatment.Enasidenib mesylate therapy, particularly at a dose of 100 mg/kg bid, applied to mice engrafted with Mx1-Cre IDH2R140QFlt3ITD AML cells, markedly reduces 2-hydroxyglutarate (2-HG) levels, consistent with on-target inhibition. Enasidenib effectively inhibits the production of 2-HG mediated by mutant IDH2[2].