The Discovery of Potential MDM2 Inhibitors: A Combination of Pharmacophore Modeling, Virtual Screening, Molecular Docking Studies, and in vitro/in vivo Biological Evaluation

Abstract

Small‐molecule inhibitors of MDM2 that block the MDM2‐p53 protein‐protein interaction have been considered as potential therapeutic agents for the treatment of cancer. Here, we identify five highly potent inhibitors of MDM2 (termed as WY 1–5) that display significant inhibitory effects on MDM2‐p53 interaction by using a combined strategy of pharmacophore modeling, virtual screening, and molecular docking studies. Among them, WY‐5 is the most active MDM2 inhibitor with an IC50 value of 14.1±2.8 nM. Moreover, WY‐5 significantly up‐regulate the protein level of p53 in SK‐Hep‐1 cells harboring wild‐type p53. In vitro anticancer study reveals that WY‐5 markedly inhibits the survival of SK‐Hep‐1 cells. In vivo anticancer study suggests that WY‐5 significantly inhibits the growth of SK‐Hep‐1 cells‐derived xenograft in nude mice, with no observable toxicity. Our results demonstrate that WY‐5 may be a promising candidate for the treatment of cancer harboring wild‐type p53.