Illudin S inhibits p53-Mdm2 interaction for anticancer efficacy in colorectal cancer

The impairment of the p53 pathway was once regarded as inadequately druggable due to the specificity of the p53 structure, its flat surface lacking an ideal drug-binding site, and the difficulty in reinstating p53 function. However, renewed interest in p53-based therapies has emerged, with promising approaches targeting p53 and ongoing clinical trials investigating p53-based treatments across various cancers. Despite significant progress in p53-targeted therapies, challenges persist in identifying effective therapeutic targets within the p53 pathway. In this study, we implemented a molecular screening system to effectively discover p53 activator. As a result, illudin S was identified as a potential inhibitor of the p53-Mdm2 interaction. This compound is particularly intriguing due to its well-documented anti-cancer effects, despite the ambiguity surrounding its precise mechanism of action. Illudin S demonstrated a direct binding affinity to the Mdm2 binding site of p53 through hydrogen bonding, which enhanced the stability and transcriptional activity of p53. The inhibition of the p53-Mdm2 interaction by illudin S led to increased p53 expression. Moreover, this inhibition effectively induced apoptosis and cell cycle arrest in CT26 colorectal cancer cells. Administration of illudin S in a colorectal cancer mouse model resulted in prolonged survival and significant tumor growth inhibition. These findings elucidate the mechanism underlying the anti-cancer effects of illudin S, specifically through its targeting of the p53-Mdm2 interaction in colorectal cancer. Consequently, illudin S emerges as a promising candidate for the development of p53-targeted cancer therapies.