IDH2 mutant inhibitor

IDH2 mutant inhibitors are a class of targeted therapies designed to selectively inhibit the neomorphic activity of mutant isocitrate dehydrogenase 2 (IDH2) enzymes. Mutations in the IDH2 gene (most commonly R140Q or R172K) lead to a gain-of-function enzyme activity that converts alpha-ketoglutarate into the oncometabolite 2-hydroxyglutarate (2-HG). Elevated levels of 2-HG cause global DNA and histone hypermethylation, which impairs normal hematopoietic differentiation and promotes leukemogenesis. By selectively binding to the mutant IDH2 enzyme, these inhibitors reduce 2-HG levels and restore cellular differentiation. The most prominent drug in this class is enasidenib (Idhifa), which was approved by the FDA in 2017 for the treatment of relapsed or refractory acute myeloid leukemia (AML) harboring an IDH2 mutation.