Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds

详细信息    查看全文

• 作者：Fangrui Wu ; Hong Jiang ; Baisong Zheng ; Mari Kogiso ; Yuan Yao ; Chao Zhou ; Xiao-Nan Li ; Yongcheng Song
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 10, 2015
• 年：2015
• 卷：58
• 期：17
• 页码：6899-6908
• 全文大小：700K
• ISSN：1520-4804

文摘

Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity of wild-type IDH1, the R132H and R132C mutant proteins can reduce 伪-ketoglutaric acid (伪-KG) to d-2-hydroxyglutaric acid (D2HG). The resulting high concentration of D2HG inhibits many 伪-KG-dependent dioxygenases, including histone demethylases, to cause broad histone hypermethylation. These aberrant epigenetic changes are responsible for the initiation of these cancers. We report the synthesis, structure鈥揳ctivity relationships, enzyme kinetics, and binding thermodynamics of a novel series of 2-thiohydantoin and related compounds, among which several compounds are potent inhibitors of mutant IDH1 with K_i as low as 420 nM. X-ray crystal structures of IDH1(R132H) in complex with two inhibitors are reported, showing their inhibitor鈥損rotein interactions. These compounds can decrease the cellular concentration of D2HG, reduce the levels of histone methylation, and suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation.