小分子p53-MDM2抑制剂先导化合物苄普地尔的研究

Discovery of bepridil as a valuable lead compound with potent p53-MDM2 inhibitory activity

目的采用老药新用药物设计方法,探寻p53-MDM2蛋白结合小分子抑制剂的先导化合物。方法通过荧光偏振(FP)法和蛋白印迹试验法,分别测定化合物的p53-MDM2蛋白结合抑制活性和相关蛋白的表达变化,采用四甲基偶氮唑盐微量酶反应比色法(MTT法)测试其体外抗肿瘤活性,并且测定人肝微粒体中代谢产物。结果发现苄普地尔具有优秀的体外抗肿瘤活性和较强的p53-MDM2蛋白结合抑制活性,能显著降低MDM2蛋白的表达,而且呈剂量依赖性。在人肝微粒体中的代谢产物主要为苯环羟基单氧化代谢产物。结论苄普地尔可作为p53-MDM2蛋白结合小分子抑制剂先导化合物,用于后续的结构优化设计研究。

Objective To find novel lead compounds as p53-MDM2 inhibitors by drug repurposing strategy.Methods The p53-MDM2 inhibitory activities of compounds were determined by FP and western blotting.MTT method was used to determine the in-vitro antitumor activities.The metabolites in human liver microsomes were tested.Results Bepridil showed excellent invitro anti-tumor activity and strong p53-MDM2 protein binding inhibitory activity,which can significantly reduce the expression of MDM2 protein in a dose-dependent manner.The metabolites in human liver microsomes are mainly benzene ring hydroxyl monooxidation metabolites.Conclusion Bepridil can be used as a lead compound for p53-MDM2 protein binding small molecule inhibitors for subsequent structural optimization design studies.