简介：针对活性氧（ROS）代谢的药物在胰腺癌治疗中取得了进展，但由于癌细胞对高浓度ROS的适应，其疗效仍然较差。细胞通过识别8-氧鸟嘌呤残基并加工严重氧化的RNA来应对ROS，这使得通过靶向8-氧鸟嘌呤调节剂来提高ROS调节药物在胰腺癌中的疗效成为可能。方法：通过癌症基因组图谱 (TCGA) 项目和基因表达综合 (GEO) 的数据集，将聚 (rC) 结合蛋白 1 (PCBP1) 确定为胰腺癌中的潜在癌基因。采用高通量虚拟筛选筛选出PCBP1的潜在抑制剂。采用计算分子动力学模拟验证了两种化合物与PCBP1之间的稳定相互作用及其构效关系。进行体外实验以验证水飞蓟汀的功能。结果：在这项研究中，我们确定 PCBP1 是胰腺癌的潜在癌基因。通过应用高通量虚拟筛选，我们确定化合物 102 和化合物 934（水飞蓟汀）为潜在的 PCBP1 抑制剂。计算分子动力学模拟和虚拟丙氨酸诱变验证了 PCBP1 和两种已鉴定化合物之间的结构-活性相关性。这两种化合物干扰 PCBP1-RNA 相互作用，损害 PCBP1 处理 RNA 的能力，导致细胞内 R 环积累。化合物 934 与 ROS 剂过氧化氢协同作用，可显着改善胰腺癌细胞诱导的细胞死亡。讨论：我们的结果为开发针对 PCBP1 的药物提供了宝贵的见解，并确定了有前景的胰腺癌 ROS 调节药物的协同药物。版权所有 © 2024 Qiao、Xu、Zhang、Wang、Jiang、Chen、Zhou、Jia 和 Cao。

Introduction: Drugs that target reactive oxygen species (ROS) metabolism have progressed the treatment of pancreatic cancer treatment, yet their efficacy remains poor because of the adaptation of cancer cells to high concentration of ROS. Cells cope with ROS by recognizing 8-oxoguanine residues and processing severely oxidized RNA, which make it feasible to improve the efficacy of ROS-modulating drugs in pancreatic cancer by targeting 8-oxoguanine regulators. Methods: Poly(rC)-binding protein 1 (PCBP1) was identified as a potential oncogene in pancreatic cancer through datasets of The Cancer Genome Atlas (TCGA) project and Gene Expression Omnibus (GEO). High-throughput virtual screening was used to screen out potential inhibitors for PCBP1. Computational molecular dynamics simulations was used to verify the stable interaction between the two compounds and PCBP1 and their structure-activity relationships. In vitro experiments were performed for functional validation of silychristin. Results: In this study, we identified PCBP1 as a potential oncogene in pancreatic cancer. By applying high-throughput virtual screening, we identified Compound 102 and Compound 934 (silychristin) as potential PCBP1 inhibitors. Computational molecular dynamics simulations and virtual alanine mutagenesis verified the structure-activity correlation between PCBP1 and the two identified compounds. These two compounds interfere with the PCBP1-RNA interaction and impair the ability of PCBP1 to process RNA, leading to intracellular R loop accumulation. Compound 934 synergized with ROS agent hydrogen peroxide to strongly improve induced cell death in pancreatic cancer cells. Discussion: Our results provide valuable insights into the development of drugs that target PCBP1 and identified promising synergistic agents for ROS-modulating drugs in pancreatic cancer.Copyright © 2024 Qiao, Xu, Zhang, Wang, Jiang, Chen, Zhou, Jia and Cao.