Language
English
Publication Date
1-1-2023
Journal
Frontiers in Oncology
DOI
10.3389/fonc.2023.1229696
PMID
37593097
PMCID
PMC10430779
PubMedCentral® Posted Date
8-1-2023
PubMedCentral® Full Text Version
Post-Print
Abstract
Introduction
The p53-Y220C mutation is one of the most common mutations that play a major role in cancer progression.
Methods
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.
Results
We identified one compound, H3, that preferentially killed cells with the p53-Y220C 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 p53-Y220C-positive cells.
Conclusion
AI enabled the discovery of the H3 compound that selectively reactivates the p53-Y220C mutant and inhibits tumor development in mice.
Keywords
mutant p53, Y220C, artificial intelligence, small molecule inhibitors, apoptosis
Published Open-Access
yes
Recommended Citation
Zhou, Shan; Chai, Dafei; Wang, Xu; et al., "AI-Powered Discovery of a Novel p53-Y220C Reactivator" (2023). Faculty and Staff Publications. 1230.
https://digitalcommons.library.tmc.edu/baylor_docs/1230