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.
Keywords: Colorectal cancer; Illudin S; P53 ubiquitination; P53-Mdm2 inhibitor; Virtual screening.
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