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 IC 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 IC 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 IC values of 18.47±0.75?μm and 31.62±1.96?μm， respectively.