Isocitrate dehydrogenase (IDH), one of the key enzymes in the citric acid cycle. And it catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) generating carbon dioxide and NADPH/NADH. IDHs belong to a large ancient family of enzymes that play central roles in energy metabolism, amino acid biosynthesis and vitamin production.

IDH protein family consists of three self-regulating enzymes (IDH1, IDH2, and IDH3). IDH2 is nicotinamide adenine dinucleotide phosphate (NADP)-dependent enzymes that catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG), while producing NADPH either in peroxisomes and the cytosol (IDH1) or in mitochondria (IDH2). Mutations in IDH1 and IDH2 have been demonstrated in a variety of malignancies. IDH inhibitors have engendered hope in IDH1/2 mutant myeloid malignancies.

Enasidenib is an Oral IDH2 Mutant Enzymes Inhibitor for Myeloid Leukemia Research

Enasidenib is an potent, reversible and selective inhibitor of the IDH2 mutant enzymes. And it is orally active with IC50s of 100 and 400 nM against IDH2R140Q and IDH2R172K, respectively.

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. And it increases in the CD11b+ population and decreases in the c-Kit+ population in the peripheral blood at 2wks.

In Vivo, 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 (10mg/kg or 100mg/kg bid) leads to a reduction in 2-HG in vivo. Moreover, Enasidenib restores megakaryocyte-erythroid progenitor (MEP) differentiation that is suppressed by mutant IDH2 expression. Enasidenib (100mg/kg bid) markedly reduces 2-hydroxyglutarate (2-HG) levels consistent with on target inhibition in mice engrafted with Mx1-Cre IDH2R140QFlt3ITD AML cells. And it inhibits mutant IDH2-mediated 2-HG production.

In conclusion, Enasidenib is an oral IDH2 mutant enzymes inhibitor for myeloid leukemia research.


[1]. Blood 2014 124(21):437.