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The Evolving Landscape in the Development of Isocitrate Dehydrogenase Mutant Inhibitors

[ Vol. 16 , Issue. 16 ]

Author(s):

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

Abstract:


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.

Keywords:

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

Affiliation:

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



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