Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors of p53–MDM2 Protein–Protein Interaction

• DOI: 10.1021/jm300969t
• Publication Date: 2012-10-09T17:17:03Z
• Authors: Chunlin Zhuang; Zhenyuan Miao; Lingjian Zhu; Guoqiang Dong; Zizhao Guo; Shengzheng Wang; Yongqiang Zhang; Yuelin Wu; Jianzhong Yao; Chunquan Sheng; Wannian Zhang
• Keywords: MDMX; Lead compound; Structure–activity relationship

The p53-MDM2 interaction has been proved to be a valuable target develop effective antitumor agents. Novel inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. nanomolar inhibitor 5 possessed good inhibitory activity (K(i) = 780 nM) due its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led the discovery of number highly potent derivatives improved in vitro antiproliferative potency. Compounds 41 260.0 60a 150.0 showed selective against tumor cells deleted p53. In addition, these two compounds also effectively inhibited growth A549 xenograft model. Interestingly, compound was MDM2/MDMX dual inhibitor. novel represent promising lead structures for development