Discovery of SCY45, a Natural Small‐Molecule MDM2‐p53 Interaction Inhibitor

The disruption of the MDM2‐p53 interaction has been regarded as an attractive strategy for anticancer drug discovery. Here, the natural small‐molecule SCY45 was identified as a potent MDM2‐p53 interaction inhibitor based on fluorescence polarization and molecular modeling. SCY45 inhibited the MDM2‐p53 interaction with an IC₅₀ value of 4.93±0.08 μm . The structural modeling results showed that SCY45 not only had high structural similarity with nutlin‐3a, a well‐reported MDM2‐P53 interaction inhibitor, but also bound to the p53 binding pocket of MDM2 with a binding mode similar to that of nutlin‐3a. Moreover, SCY45 reduced the cell viability in cancer cells with MDM2 gene amplification. SCY45 showed the highest inhibition for SJSA‐1 cells, which exhibit excessive MDM2 gene amplification, with an IC₅₀ value of 7.54±0.29 μm , whereas SCY45 showed a weaker inhibition for 22Rv1 cells and A549 cells, which have a single copy of the MDM2 gene, with IC₅₀ values of 18.47±0.75 μm and 31.62±1.96 μm , respectively.