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.
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