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.
Mini-Reviews in Medicinal Chemistry
Title:The Evolving Landscape in the Development of Isocitrate Dehydrogenase Mutant Inhibitors
Volume: 16 Issue: 16
Author(s): Jiao Chen, Jie Yang and Peng Cao
Affiliation:
Keywords: Cancer, drug discovery, IDH1, IDH2, inhibitor, mutant.
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.
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Cite this article as:
Chen Jiao, Yang Jie and Cao Peng, The Evolving Landscape in the Development of Isocitrate Dehydrogenase Mutant Inhibitors, Mini-Reviews in Medicinal Chemistry 2016; 16 (16) . https://dx.doi.org/10.2174/1389557516666160609085520
DOI https://dx.doi.org/10.2174/1389557516666160609085520 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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