AI-powered Discovery of a Novel P53-Y220C Reactivator

Overview

Journal Front Oncol

Specialty Oncology

Date 2023 Aug 18

PMID 37593097

Authors

Shan Zhou

Dafei Chai

Xu Wang

Praveen Neeli

Xinfang Yu

Aram Davtyan

Ken Young

Yong Li

Affiliations

Soon will be listed here.

Abstract

Introduction: The 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 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 -positive cells.

Conclusion: AI enabled the discovery of the H3 compound that selectively reactivates the p53-Y220C mutant and inhibits tumor development in mice.

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