The Evolving Landscape in the Development of Isocitrate Dehydrogenase Mutant Inhibitors.
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.
Jiao
J
Chen
Jie
J
Yang
Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu, China. pcao79@yahoo.com.
Peng
P
Cao
D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D050505:Mutant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics
D004791:Enzyme Inhibitors; D050505:Mutant Proteins; D007521:Isocitrate Dehydrogenase