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The Evolving Landscape in the Development of Isocitrate Dehydrogenase Mutant Inhibitors

[ Vol. 16 , Issue. 16 ]


Jiao Chen, Jie Yang and Peng Cao   Pages 1344 - 1358 ( 15 )


Isocitrate dehydrogenase (IDH) is a metabolic enzyme that converts isocitrate to α-ketoglutarate (α-KG). Genetic gain-of-function mutations in IDH1 and IDH2 confer a neomorphic activity that allow reduction of α -KG to (R)-2- hydroxyglutarate, the accumulation of which results in the development of cancers like low grade gliomas and leukemia. After treatment with AG-221 in clinical trials, a first-in-class inhibitor of mutated IDH2, 29 patients with acute myeloid leukemia or myelodysplastic syndrome experience complete remissions and the overall response rate is 59/159 (37%). Thus, IDH mutants have become intriguing targets for cancer therapeutics. In addition to providing a brief summary of IDH mutations, this review describes known inhibitors with potential activities against IDH mutants such as AG-120, AG-221, AG-881 and AGI-6780. The evolving landscape of IDH mutant inhibitors provides us an outlook on the discovery of novel, safer, and more effective cancer treatment strategies.


Cancer, drug discovery, IDH1, IDH2, inhibitor, mutant.


Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu, China.

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