Isocitrate dehydrogenase [NADP+] 1 (IDH1) (mutant) (IDH1 (mutant))

Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that normally catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) while reducing NADP+ to NADPH (UniProt P48735). Mutations in the IDH1 gene, most commonly at the R132 residue, confer a neomorphic enzymatic activity that leads to the production of the oncometabolite (R)-2-hydroxyglutarate (2-HG) (PubMed: 19228930). Elevated levels of 2-HG competitively inhibit α-KG-dependent dioxygenases, including histone demethylases and TET family DNA hydroxylases, resulting in epigenetic dysregulation and impaired cellular differentiation (PubMed: 20164835). These mutations are frequently observed in various malignancies, including low-grade gliomas, secondary glioblastomas, acute myeloid leukemia (AML), and cholangiocarcinoma (PubMed: 23541368). Therapeutic targeting of mutant IDH1 involves small-molecule inhibitors that bind to the enzyme's active site or allosteric sites to suppress 2-HG production. By reducing 2-HG levels, these inhibitors promote the differentiation of malignant cells and inhibit tumor growth. Clinical use of IDH1 inhibitors like ivosidenib has shown efficacy in treating IDH1-mutant AML and cholangiocarcinoma, though challenges such as differentiation syndrome and acquired resistance remain (FDA: Tibsovo Prescribing Information).

Other names

IDH1Isocitrate dehydrogenase 1 (NADP+), cytosolicNADP(+)-specific isocitrate dehydrogenase, cytosolicIDPIDPCPICDOxalosuccinate decarboxylase

Small molecule inhibition of the mutant IDH1 enzyme to block the neomorphic conversion of alpha-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate (2-HG) (PubMed: 23541368).