Journal
CURRENT TOPICS IN MEDICINAL CHEMISTRY
Volume 18, Issue 6, Pages 505-524Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1568026618666180518091144
Keywords
Isocitrate dehydrogenase; mutation; Glioma; AML; cancer metabolism; mIDH inhibitors; cancer
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Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that catalyze the conversion of isocitrate to alpha-ketoglutarate (alpha KG). 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 alpha KG 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.
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