Isocitrate dehydrogenase 1 (IDH1) R132H mutant (IDH1-R132H)

Isocitrate dehydrogenase 1 (IDH1) R132H is a specific mutant form of the cytosolic enzyme IDH1, characterized by the substitution of arginine with histidine at residue 132 [1, 17]. This mutation is a critical driver in several malignancies, including over 70% of lower-grade gliomas and secondary glioblastomas, as well as a subset of acute myeloid leukemia (AML) and cholangiocarcinoma [2, 12]. While the wild-type enzyme normally catalyzes the conversion of isocitrate to alpha-ketoglutarate (α-KG), the R132H mutation confers a neomorphic gain-of-function that reduces α-KG to the oncometabolite D-2-hydroxyglutarate (D-2HG) [1, 10]. The accumulation of D-2HG competitively inhibits α-KG-dependent dioxygenases, leading to widespread DNA and histone hypermethylation and a subsequent block in cellular differentiation [3, 12]. Targeting this mutant enzyme has become a cornerstone of precision oncology, with several small-molecule inhibitors developed to specifically block its aberrant activity [1, 5]. Drugs such as ivosidenib and vorasidenib work by binding to the mutant protein and reducing D-2HG levels, which can reverse the differentiation block and inhibit tumor growth [1, 18]. Clinical use of these inhibitors requires molecular screening for the R132H mutation, which also serves as a significant diagnostic and prognostic biomarker [3, 7]. Despite their efficacy, therapeutic challenges include managing differentiation syndrome in hematologic patients and ensuring sufficient blood-brain barrier penetration for treating CNS tumors [2, 18].

Other names

mIDH1Mutant IDH1IDH1 R132HIsocitrate dehydrogenase [NADP] cytoplasmic R132H

Inhibition of the neomorphic enzymatic activity of the mutant IDH1 protein, thereby reducing the production of the oncometabolite D-2-hydroxyglutarate (D-2HG) and restoring normal cellular differentiation.