State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, 999078, Macau.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
Biochem Biophys Res Commun. 2021 Apr 30;551:38-45. doi: 10.1016/j.bbrc.2021.02.112. Epub 2021 Mar 11.
Isocitrate dehydrogenase 1 (IDH1) mutant R132H, promoting the oncometabolite D-2-hydroxyglutarate (D2HG), is a driver mutation and an emerging therapeutic target in glioma. This study identified a novel mutant IDH1 inhibitor, WM17, by virtual screening and enzymatic confirmation. It could bind to and increase mutant IDH1 protein's thermostability in both endogenous heterozygous cells and exogenous overexpressed cells. Consequently, WM17 reversed the accumulation of D2HG and histone hypermethylation in IDH1 mutated cells. Finally, we concluded that WM17 significantly inhibited cell migration in IDH1 mutated glioma cells, although it has no apparent effect on cell proliferation. Further studies are guaranteed toward the development of WM17 as a therapeutic agent for IDH1 mutated glioma.
异柠檬酸脱氢酶 1（IDH1）突变体 R132H 促进致癌代谢物 D-2-羟戊二酸（D2HG）的产生，是胶质瘤中的驱动突变和新兴治疗靶点。本研究通过虚拟筛选和酶学确证，发现了一种新型的突变型 IDH1 抑制剂 WM17。它可以结合并增加内源性杂合细胞和外源性过表达细胞中突变型 IDH1 蛋白的热稳定性。结果，WM17 逆转了 IDH1 突变细胞中 D2HG 和组蛋白过度甲基化的积累。最后，我们得出结论，WM17 显著抑制了 IDH1 突变型神经胶质瘤细胞的迁移，尽管它对细胞增殖没有明显影响。进一步的研究保证了 WM17 作为 IDH1 突变型神经胶质瘤治疗剂的开发。
