Isocitrate dehydrogenase 1 and 2 mutants (mIDH1/2)

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are metabolic enzymes that normally catalyze the conversion of isocitrate to alpha-ketoglutarate (a-KG) while producing NADPH. Specific somatic mutations in these enzymes, most commonly at residues R132 in IDH1 and R140 or R172 in IDH2, confer a neomorphic gain-of-function that leads to the abnormal production of the oncometabolite D-2-hydroxyglutarate (D-2HG). High levels of D-2HG competitively inhibit a-KG-dependent dioxygenases, including DNA and histone demethylases, which results in global epigenetic hypermethylation and a block in cellular differentiation. This metabolic reprogramming is a key driver in several malignancies, including acute myeloid leukemia (AML), low-grade gliomas, and secondary glioblastomas. Therapeutic targeting of these mutants involves small-molecule inhibitors like ivosidenib and enasidenib, which bind to the mutant enzyme's active site to suppress D-2HG production. By lowering D-2HG levels, these drugs facilitate the maturation of malignant cells into functional, non-proliferating cells. Clinical use of these inhibitors has shown significant efficacy, though it is associated with unique safety concerns such as differentiation syndrome, particularly in hematologic settings.

Other names

Mutant IDH1Mutant IDH2mIDH1mIDH2Isocitrate dehydrogenase 1 (NADP+), soluble mutantIsocitrate dehydrogenase 2 (NADP+), mitochondrial mutant

Selective inhibition of the neomorphic enzymatic activity of mutant IDH1 or IDH2 proteins to reduce the production of the oncometabolite D-2-hydroxyglutarate (D-2HG), thereby reversing epigenetic dysregulation and restoring normal cellular differentiation.