多靶点抑制剂是解决分子靶向抗肿瘤药物耐药性的重要途径之一，本课题组在p53-MDM2小分子抑制剂抗肿瘤药物研究过程中，发现吡咯酮类化合物MZY167具有非常强的激活p53信号通路和抑制NF-kappa B信号通路双重调节作用。通过计算机靶标筛选研究和分子生物学的初步验证，意外地发现MZY167的R和S异构体分别专一性作用于两个信号通路的关键调控蛋白MDM2和IKK beta激酶。本课题拟通过分子药理学和分子动力学的研究，揭示R、S异构体对p53及NF-kappa B信号通路交互应答作用的分子机理，识别确认作用靶标和作用部位，研究确定两异构体与靶标的结合模式，以MZY167为先导物，设计合成对p53与NF-kappa B信号通路交互应答双靶点作用的抗肿瘤药候选化合物，为创制一类手性对应体协同作用于MDM2和IKK beta两个靶标、高效、低毒、抗耐药的抗肿瘤新药奠定基础。

In most cases, the multi-target drugs have much more potential to overcome drug resistance than single antitumor agents. Based on the discovery of novel p53-MDM2 inhibitors, the pyrrolidone compound MZY167 was found to inhibit two pathways of p53 and NF-kappa B which are critical for cancer cell survival. To our surprise, the key proteins MDM2 and IKK beta of these two pathways were identified in silico as potential targets for the R-isomer and S-isomer of the racemic compound MZY167, respectively. In addition, specific binding of the two isomers was confirmed by pharmacological experiments. This proposal aim to investigate the effects of these two isomers on the transcriptional regulation of p53 and NF kappa B signal pathways by a series of molecular pharmacology experiments. Molecular dynamics simulations will be used to clarify the binding modes of the isomers with the targets. As a result,novel pyrrol-2(5H)-one derivatives as dual inhibitors of MDM2 and IKK beta with increased antitumor activity and lower toxicity will be identified.