Discovery of 1,2-Naphthoquinone Derivatives as Potent p53-MDM2 Interaction Inhibitors

摘要

The p53 protein is one of the most famous tumor suppressors and plays a critical role in tumor prevention by inducing the expression of genes involved in cell cycle arrest,apoptosis,and cellular senescence.Uncontrolled activation of p53 protein is blocked by the interactions with its negative regulator MDM2.MDM2 is an E3 ubiquitin ligase that exhibits a high binding affinity for p53 protein and facilitates its ubiquitin-dependent degradation.Thus,the activation of p53 by disrupting its interactions with MDM2 has been considered to be one of the promising therapeutic strategies to treat cancers.Several small molecule inhibitors to disrupt the p53-MDM2 interactions have been reported to exhibit promising anti-tumor activity both in vitro and in vivo.Nutlins with a cis-imidazoline core structure were the first potent and selective MDM2 antagonists,demonstrating reactivation of p53 signaling pathway and tumor regressions in mouse xenograft models.RG7112,which was prepared by further optimizing Nutlins,entered clinical trials as a p53-MDM2 interaction inhibitor for treating multiple human cancers.Other excellent examples for p53-MDM2 inhibitors are spirooxindole-containing small molecules such as MI-63,MI-218,and MI-888.