Isocitrate dehydrogenase [NADP] cytoplasmic R132H mutant (IDH1 R132H)

Isocitrate dehydrogenase 1 (IDH1) is a key metabolic enzyme that normally catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) while reducing NADP+ to NADPH [1, 12]. The R132H mutation is a specific somatic alteration where arginine at position 132 is replaced by histidine, a change that occurs in the majority of low-grade gliomas and a subset of acute myeloid leukemias (AML) [1, 3]. This mutation results in a gain-of-function neomorphic activity, enabling the enzyme to convert α-KG into the oncometabolite D-2-hydroxyglutarate (2-HG) [2, 7]. The accumulation of 2-HG leads to the competitive inhibition of α-KG-dependent dioxygenases, such as TET2 and various histone demethylases, which causes global DNA and histone hypermethylation and blocks normal cellular differentiation [4, 13]. Pharmacological inhibition of the mutant IDH1 R132H protein aims to lower 2-HG levels, thereby reversing the epigenetic block and inducing the differentiation of cancer cells into more mature, non-proliferative states [2, 6]. Several targeted inhibitors, including Ivosidenib and Vorasidenib, have been developed and approved for clinical use in patients harboring this specific mutation [2, 7].

Other names

IDH1-R132HmIDH1Mutant IDH1R132H IDH1Isocitrate dehydrogenase 1 R132H

Inhibition of the neomorphic enzymatic activity of the mutant IDH1 protein to reduce the production of the oncometabolite D-2-hydroxyglutarate (2-HG) and restore normal cellular differentiation.