AUTHOR=Zhou Shan , Chai Dafei , Wang Xu , Neeli Praveen , Yu Xinfang , Davtyan Aram , Young Ken , Li Yong 

TITLE=AI-powered discovery of a novel p53-Y220C reactivator

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1229696

DOI=10.3389/fonc.2023.1229696

ISSN=2234-943X

ABSTRACT=<sec><title>Introduction</title><p>The <italic>p53-Y220C</italic> mutation is one of the most common mutations that play a major role in cancer progression.</p></sec><sec><title>Methods</title><p>In this study, we applied artificial intelligence (AI)-powered virtual screening to identify small-molecule compounds that specifically restore the wild-type p53 conformation from p53-Y220C. From 10 million compounds, the AI algorithm selected a chemically diverse set of 83 high-scoring hits, which were subjected to several experimental assays using cell lines with different p53 mutations.</p></sec><sec><title>Results</title><p>We identified one compound, H3, that preferentially killed cells with the <italic>p53-Y220C</italic> mutation compared to cells with other p53 mutations. H3 increased the amount of folded mutant protein with wild-type p53 conformation, restored its transcriptional functions, and caused cell cycle arrest and apoptosis. Furthermore, H3 reduced tumorigenesis in a mouse xenograft model with <italic>p53-Y220C</italic>-positive cells.</p></sec><sec><title>Conclusion</title><p>AI enabled the discovery of the H3 compound that selectively reactivates the p53-Y220C mutant and inhibits tumor development in mice.</p></sec>