Isocitrate dehydrogenase 2 (NADP+), mitochondrial (mutant form) (IDH2)

Mutant isocitrate dehydrogenase 2 (IDH2) is a mitochondrial enzyme that plays a critical role in the pathogenesis of several cancers, most notably acute myeloid leukemia (AML). In its wild-type form, IDH2 catalyzes the conversion of isocitrate to alpha-ketoglutarate (α-KG) as part of the tricarboxylic acid (TCA) cycle. However, somatic mutations at specific arginine residues (R140 and R172) confer a neomorphic gain-of-function activity, allowing the enzyme to convert α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG). The accumulation of 2-HG leads to epigenetic dysregulation by inhibiting α-KG-dependent dioxygenases, which results in DNA and histone hypermethylation and a block in myeloid differentiation. Enasidenib is a potent, selective, oral small-molecule inhibitor that allosterically binds to the mutant IDH2 homodimer or heterodimer. By inhibiting the production of 2-HG, enasidenib alleviates the differentiation block, allowing leukemic blasts to mature into functional myeloid cells.

Other names

mIDH2Isocitrate dehydrogenase [NADP], mitochondrialIsocitrate dehydrogenase (NADP(+)) 2, mitochondrialIDPICD-MIDHMmNADP-IDHD2HGA2

Selective allosteric inhibition of mutant IDH2 enzyme to reduce production of the oncometabolite 2-hydroxyglutarate (2-HG), thereby restoring alpha-ketoglutarate-dependent dioxygenase activity and inducing cellular differentiation.