Isocitrate dehydrogenase (mutant) (mIDH)

Mutant isocitrate dehydrogenase (mIDH) refers to specific oncogenic mutations in the enzymes IDH1 and IDH2, which normally catalyze the conversion of isocitrate to alpha-ketoglutarate (Dang et al., Nature, 2009). In various cancers, mutations such as IDH1 R132 or IDH2 R140/R172 confer a neomorphic activity that converts alpha-ketoglutarate into the oncometabolite D-2-hydroxyglutarate (2-HG) (Ward et al., Cancer Cell, 2010). The accumulation of 2-HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, leading to DNA and histone hypermethylation, which blocks cellular differentiation and promotes tumorigenesis (Xu et al., Cancer Cell, 2011). This metabolic pathway is a key driver in malignancies such as acute myeloid leukemia, glioma, and cholangiocarcinoma. Therapeutic targeting of these mutant enzymes with small-molecule inhibitors, such as ivosidenib and enasidenib, aims to lower 2-HG levels and restore normal epigenetic signaling (DiNardo et al., N Engl J Med, 2018). These treatments have demonstrated the ability to induce terminal differentiation of malignant cells, providing a precision medicine approach for patients harboring these specific mutations (Stein et al., Blood, 2017).

Other names

Mutant IDHmIDH1mIDH2Isocitrate dehydrogenase 1 (mutant)Isocitrate dehydrogenase 2 (mutant)IDH1/2 mutant

Small-molecule inhibition of the neomorphic activity of mutant IDH1 or IDH2 enzymes to prevent the production of the oncometabolite D-2-hydroxyglutarate (2-HG), thereby restoring normal epigenetic signaling and promoting cellular differentiation.