Isocitrate dehydrogenase (NADP(+)) 1 (IDH1) and Isocitrate dehydrogenase (NADP(+)) 2 (IDH2) (IDH1/2)

Isocitrate dehydrogenase (NADP(+)) 1 (IDH1) and Isocitrate dehydrogenase (NADP(+)) 2 (IDH2) are metabolic enzymes that normally catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) (UniProt P48735, P48739). In many gliomas and other malignancies, specific mutations in these enzymes—most commonly IDH1 R132H—result in a neomorphic gain-of-function that produces the oncometabolite D-2-hydroxyglutarate (2-HG) (PubMed: 19935646). The accumulation of 2-HG leads to a distinct metabolic phenotype characterized by the inhibition of α-KG-dependent enzymes, resulting in DNA and histone hypermethylation and a block in cellular differentiation (PubMed: 20164831). This 'mutant-dependent metabolic phenotype' is a key driver of gliomagenesis and creates specific metabolic vulnerabilities in tumor cells. Targeted therapies, such as vorasidenib and ivosidenib, inhibit these mutant enzymes to reduce 2-HG levels and promote tumor cell differentiation (PubMed: 37272513). Clinical evidence suggests that targeting this metabolic pathway can significantly delay disease progression in patients with IDH-mutant gliomas.

Other names

IDH1IDH2Isocitrate dehydrogenase (NADP(+)) 1Isocitrate dehydrogenase (NADP(+)) 2Mutant IDHNADP(+)-specific isocitrate dehydrogenase

Inhibition of the neomorphic activity of mutant IDH1 and IDH2 enzymes to reduce the production of the oncometabolite D-2-hydroxyglutarate (2-HG).