Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases: Synthesis, Structure鈥揂ctivity Relationship, and Selective Antitumor Activity

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• 作者：Zhen Liu ; Yuan Yao ; Mari Kogiso ; Baisong Zheng ; Lisheng Deng ; Jihui J. Qiu ; Shuo Dong ; Hua Lv ; James M. Gallo ; Xiao-Nan Li ; Yongcheng Song
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 23, 2014
• 年：2014
• 卷：57
• 期：20
• 页码：8307-8318
• 全文大小：494K
• ISSN：1520-4804

文摘

Mutations of isocitrate dehydrogenase 1 (IDH1) are frequently found in certain cancers such as glioma. Different from the wild-type (WT) IDH1, the mutant enzymes catalyze the reduction of 伪-ketoglutaric acid to d-2-hydroxyglutaric acid (D2HG), leading to cancer initiation. Several 1-hydroxypyridin-2-one compounds were identified to be inhibitors of IDH1(R132H). A total of 61 derivatives were synthesized, and their structure鈥揳ctivity relationships were investigated. Potent IDH1(R132H) inhibitors were identified with K_i values as low as 140 nM, while they possess weak or no activity against WT IDH1. Activities of selected compounds against IDH1(R132C) were found to be correlated with their inhibitory activities against IDH1(R132H), as well as cellular production of D2HG, with R² of 0.83 and 0.73, respectively. Several inhibitors were found to be permeable through the blood鈥揵rain barrier in a cell-based model assay and exhibit potent and selective activity (EC₅₀ = 0.26鈥?.8 渭M) against glioma cells with the IDH1 R132H mutation.