Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that catalyze
the conversion of isocitrate to α-ketoglutarate (αKG). IDH1 and IDH2 regulate several cellular processes,
including oxidative respiration, glutamine metabolism, lipogenesis, and cellular defense against
oxidative damage. Mutations in IDH1 and IDH2 have recently been observed in multiple tumors, including
gliomas, acute myeloid leukemia, myelodysplastic syndromes, and chondrosarcoma. IDH1 and
IDH2 mutations involve a gain in neomorphic activity that catalyzes αKG conversion to (R)-2-
hydroxyglutarate ((R)-2HG). IDH mutation-mediated accumulation of (R)-2HG results in epigenetic
dysregulation, altered gene expression, and a block in cellular differentiation. Targeting mutant IDH by
development of small molecule inhibitors is a rapidly emerging therapeutic approach as evidenced by
the recent approval of the first selective mutant IDH2 inhibitor AG-221 (enasidenib) for the treatment of
IDH2-mutated AML. This review will focus on mutant isocitrate dehydrogenase as a therapeutic drug
target and provides an update on selective and pan-mutant IDH1/2 inhibitors in clinical trials and other
mutant IDH inhibitors that are under development.
Keywords: Isocitrate dehydrogenase, mutation, Glioma, AML, cancer metabolism, mIDH inhibitors, cancer.
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