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
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.