通过人工智能发现一种新型p53-Y220C激活剂。
AI-powered discovery of a novel p53-Y220C reactivator.
作者信息
Zhou Shan, Chai Dafei, Wang Xu, Neeli Praveen, Yu Xinfang, Davtyan Aram, Young Ken, Li Yong
机构信息
Department of Medicine, Section of Epidemiology and Population Sciences, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States.
Atomwise Inc., San Francisco, CA, United States.
出版信息
Front Oncol. 2023 Aug 1;13:1229696. doi: 10.3389/fonc.2023.1229696. eCollection 2023.
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.
引言
该突变是在癌症进展中起主要作用的最常见突变之一。
方法
在本研究中，我们应用人工智能驱动的虚拟筛选来鉴定能特异性地将p53-Y220C恢复为野生型p53构象的小分子化合物。从1000万个化合物中，人工智能算法选择了一组化学性质多样的83个高分命中化合物，使用具有不同p53突变的细胞系对其进行了多种实验检测。
结果
我们鉴定出一种化合物H3，与具有其他p53突变的细胞相比，它优先杀死具有该突变的细胞。H3增加了具有野生型p53构象的折叠突变蛋白的量，恢复了其转录功能，并导致细胞周期停滞和凋亡。此外，H3在具有该阳性细胞的小鼠异种移植模型中减少了肿瘤发生。
结论
人工智能促成了H3化合物的发现，该化合物能选择性地重新激活p53-Y220C突变体并抑制小鼠肿瘤发展。
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