Development of Novel Therapeutics Targeting Isocitrate Dehydrogenase Mutations in Cancer

Author(s): Horrick Sharma*

Journal Name: Current Topics in Medicinal Chemistry

Volume 18 , Issue 6 , 2018

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Graphical Abstract:


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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Article Details

Year: 2018
Page: [505 - 524]
Pages: 20
DOI: 10.2174/1568026618666180518091144
Price: $65

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