Isocitrate dehydrogenase 1 (IDH1) (IDH1)

Isocitrate dehydrogenase 1 (IDH1) is a critical metabolic enzyme primarily located in the cytoplasm and peroxisomes, where it catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) while generating NADPH [2, 4]. In various cancers, somatic hotspot mutations—most commonly at the arginine 132 (R132) residue—confer a neomorphic gain-of-function activity to the enzyme [1, 8]. This mutant form of IDH1 converts α-KG into the oncometabolite (R)-2-hydroxyglutarate (2-HG), which accumulates to high levels and competitively inhibits α-KG-dependent dioxygenases, including TET DNA demethylases and histone demethylases [9, 13]. The resulting epigenetic dysregulation leads to DNA and histone hypermethylation, which blocks normal cellular differentiation and promotes tumorigenesis in diseases such as acute myeloid leukemia (AML), glioma, and cholangiocarcinoma [1, 14]. Targeted inhibitors like ivosidenib and olutasidenib bind to the mutant IDH1 enzyme to suppress 2-HG production, thereby restoring the ability of malignant cells to undergo terminal differentiation [7, 10]. Clinical use of these inhibitors is associated with specific safety concerns, most notably differentiation syndrome in AML patients, which requires prompt management with corticosteroids [17, 19].

Other names

Isocitrate dehydrogenase [NADP] cytoplasmicIsocitrate dehydrogenase 1 (NADP+), solubleNADP(+)-specific ICDHOxalosuccinate decarboxylaseIDPIDPCPICDIDCDMutant IDH1

Selective inhibition of the mutant IDH1 enzyme to reduce the production of the oncometabolite 2-hydroxyglutarate (2-HG), thereby reversing the block in cellular differentiation and restoring normal epigenetic signaling.