ATC Group: L01XM Isocitrate dehydrogenase (IDH) inhibitors

Enasidenib is a small molecule inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme. Enasidenib targets the mutant IDH2 variants R140Q, R172S, and R172K at approximately 40-fold lower concentrations than the wild-type enzyme in vitro. Inhibition of the mutant IDH2 enzyme by enasidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, enasidenib decreased 2-HG levels, reduced blast counts and increased percentages of mature myeloid cells.

Ivosidenib is an inhibitor of the mutant IDH1 enzyme. Mutant IDH1 converts alpha- ketoglutarate (αKG) to 2-hydroxyglutarate (2-HG) which blocks cellular differentiation and promotes tumorigenesis in both hematologic and non-hematologic malignancies. The mechanism of action of ivosidenib beyond its ability to reduce 2-HG and restore cellular differentiation is not fully understood across indications.

Vorasidenib is an inhibitor that targets the mutant IDH1 and IDH2 enzymes. In patients with astrocytoma or oligodendroglioma, IDH1 and IDH2 mutations lead to overproduction of the oncogenic metabolite 2-hydroxyglutarate (2-HG), resulting in impaired cellular differentiation contributing to oncogenesis. Inhibition of the IDH1- and IDH2-mutated proteins by vorasidenib inhibits the abnormal production of 2-HG leading to differentiation of malignant cells and a reduction in their proliferation.