Isocitrate dehydrogenase 1 R132C mutant (IDH1 R132C)

The Isocitrate dehydrogenase 1 (IDH1) R132C mutant is a neomorphic enzyme that plays a critical role in the pathogenesis of several malignancies, including acute myeloid leukemia (AML), glioma, and cholangiocarcinoma [4, 8]. While wild-type IDH1 catalyzes the conversion of isocitrate to alpha-ketoglutarate (a-KG), the R132C mutation confers a gain-of-function activity that converts a-KG into the oncometabolite D-2-hydroxyglutarate (D-2HG) [13, 21]. The massive accumulation of D-2HG competitively inhibits a-KG-dependent dioxygenases, such as TET2 and histone demethylases, leading to global DNA and histone hypermethylation [10, 23]. This epigenetic dysregulation blocks normal cellular differentiation and promotes tumorigenesis [13, 15]. Therapeutic targeting of this mutant enzyme involves small-molecule inhibitors like ivosidenib and olutasidenib, which bind to the mutant protein and suppress D-2HG production [1, 7]. By lowering D-2HG levels, these drugs facilitate the differentiation of malignant cells into mature, functional cells, offering a targeted approach to treating IDH1-mutated cancers [4, 12].

Other names

mIDH1 R132CMutant isocitrate dehydrogenase 1 R132CIDH1-R132CIsocitrate dehydrogenase 1 (NADP+) R132C

Inhibition of the neomorphic enzymatic activity of the mutant IDH1 protein to reduce the production of the oncometabolite D-2-hydroxyglutarate (D-2HG), thereby reversing epigenetic hypermethylation and restoring cellular differentiation.