Emerging drug profile: Krebs cycle and cancer: IDH mutations and therapeutic implications

Mutations in IDH1 and IDH2 genes occur frequently in myeloid malignancies and certain solid tumors. IDH1 and IDH2 are enzymes that are involved in the tricarboxylic acid (TCA) cycle. Activating mutations in IDH1 and IDH2 leads to increased production of 2-hydroxygluterate and epigenetic modification, affecting cell differentiation. Small molecule inhibitors of mutated IDH1 and IDH2 have shown promising anti-cancer activity in both preclinical models and early clinical trials. Recently, enasidenib and ivosidenib, oral inhibitors of mutated IDH2 and IDH1 genes, respectively, were approved for use in relapsed or refractory acute myeloid leukemia. This review will focus on the underlying biological mechanism and clinical relevance of IDH mutations in cancer.