Isocitrate dehydrogenase [NADP] cytoplasmic (IDH1) R132 mutant (IDH1 R132)

Isocitrate dehydrogenase 1 (IDH1) is a cytoplasmic enzyme that normally catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG). Mutations at the Arginine 132 (R132) residue, most commonly R132H, confer a neomorphic gain-of-function activity that converts α-KG into the oncometabolite D-2-hydroxyglutarate (D-2HG) (Source: UniProt P48735). Accumulation of D-2HG competitively inhibits α-KG-dependent dioxygenases, including histone demethylases and TET family DNA hydroxylases, leading to DNA hypermethylation and a block in cellular differentiation (Source: PubMed PMID: 20035030). This mutation is a key driver in several malignancies, including low-grade gliomas, secondary glioblastomas, acute myeloid leukemia (AML), and cholangiocarcinoma (Source: NIH NCI). Targeted inhibitors like ivosidenib and olutasidenib bind to the mutant enzyme to suppress D-2HG production, thereby inducing clinical responses by promoting the maturation of malignant cells (Source: FDA Tibsovo Label). These therapies represent a significant advancement in precision oncology for patients harboring these specific genetic alterations.

Other names

Mutant IDH1mIDH1IDH1 R132HIDH1 R132CIDH1 R132GIDH1 R132SIDH1 R132L

Selective inhibition of the mutant IDH1 enzyme to reduce levels of the oncometabolite D-2-hydroxyglutarate (D-2HG), which restores normal cellular differentiation and inhibits tumor growth (Source: PubMed PMID: 29858362).