Inhibitors of Mutant Isocitrate Dehydrogenases 1 and 2 (mIDH1/2): An Update and Perspective
Inhibitors of Mutant Isocitrate Dehydrogenases 1 and 2 (mIDH1/2): An Update and Perspective
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DOI：
10.1021/acs.jmedchem.8b00159
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发表时间：
2018-10-25
影响因子：
7.3
通讯作者：
Zha, Xiaoming
中科院分区：
文献类型：
--
作者：
Ma, Tianfan;Zou, Fangxia;Zha, Xiaoming
异柠檬酸脱氢酶1和2（IDH 1/2）是在三羧酸循环中催化异柠檬酸转化为α-酮戊二酸（α-KG）的同二聚体酶。然而，突变体IDH 1/2（mIDH 1/2）将α-KG还原为癌代谢物2-羟基戊二酸（2-HG）。高水平的2-HG竞争性抑制参与组蛋白和DNA去甲基化的α-KG依赖性双加氧酶，从而损害正常细胞分化并促进肿瘤发展。因此，抑制这些突变酶的小分子可能在治疗上是有益的。最近，越来越多的mIDH 1/2抑制剂已被报道。本文就mIDH 1/2的分子基础、mIDH 1/2抑制剂的活性、结合方式及临床应用进展作一综述。我们指出了mIDH 1/2抑制剂未来重要的研究方向，并讨论了开发mIDH 1/2抑制剂治疗IDH 1/2突变肿瘤的潜在治疗策略。
Isocitrate dehydrogenases 1 and 2 (IDH1/2) are homodimeric enzymes that catalyze the conversion of isocitrate to alpha-ketoglutarate (alpha-KG) in the tricarboxylic acid cycle. However, mutant IDH1/2 (mIDH1/2) reduces alpha-KG to the oncometabolite 2-hydroxyglutarate (2-HG). High levels of 2-HG competitively inhibit the alpha-KGdependent dioxygenases involved in histone and DNA demethylation, thereby impairing normal cellular differentiation and promoting tumor development. Thus, small molecules that inhibit these mutant enzymes may be therapeutically beneficial. Recently, an increasing number of mIDH1/2 inhibitors have been reported. In this review, we summarize the molecular basis of mIDH1/2 and the activity, binding modes, and progress in clinical application of mIDH1/2 inhibitors. We note important future research directions for mIDH1/2 inhibitors and discuss potential therapeutic strategies for the development of mIDH1/2 inhibitors to treat IDH1/2 mutated tumors.