| Autor: |
Shan Zhou, Dafei Chai, Xu Wang, Praveen Neeli, Xinfang Yu, Aram Davtyan, Ken Young, Yong Li |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Frontiers in Oncology, Vol 13 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2234-943X |
| DOI: |
10.3389/fonc.2023.1229696 |
| Popis: |
IntroductionThe p53-Y220C mutation is one of the most common mutations that play a major role in cancer progression.MethodsIn 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.ResultsWe 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.ConclusionAI enabled the discovery of the H3 compound that selectively reactivates the p53-Y220C mutant and inhibits tumor development in mice. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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