mTOR通路的异常活化与癌症的发生和进展密切相关，尤其是结直肠癌。本研究建立了一个合理的虚拟筛选策略，并从ChemDiv数据库中获得了MT-5，这是一种具有喹啉支架的新型mTOR抑制剂。MT-5显示出强大的激酶抑制活性（IC50：8.90 μM）和抗多种癌细胞系的增殖效应，尤其是HCT-116细胞（IC50：4.61 μM），其抗增殖效应是顺铂对照（IC50：9.99 μM）的2.2倍。通过Western blot、细胞迁移、细胞周期阻滞和凋亡实验，研究了MT-5的潜在抗癌机制。体外代谢稳定性结果显示，MT-5在人造胃肠液、大鼠血浆和肝微粒体中具有良好的稳定性。此外，还从计算的角度研究了MT-5结合到mTOR蛋白结合口袋周围残基的关键贡献。版权所有 © 2023 Elsevier Inc. 保留所有权利。

The abnormal activation of the mTOR pathway is closely related to the occurrence and progression of cancer, especially colorectal cancer. In this study, a rational virtual screening strategy has been established and MT-5, a novel mTOR inhibitor with a quinoline scaffold, was obtained from the ChemDiv database. MT-5 showed potent kinase inhibitory activity (IC50: 8.90 μM) and antiproliferative effects against various cancer cell lines, especially HCT-116 cells (IC50: 4.61 μM), and this was 2.2-fold more potent than that of the cisplatin control (IC50: 9.99 μM). Western blot, cell migration, cycle arrest, and apoptosis assays were performed with HCT-116 cells to investigate the potential anticancer mechanism of MT-5. Metabolic stability results in vitro indicated that MT-5 exhibited good stability profiles in artificial gastrointestinal fluids, rat plasma, and liver microsomes. In addition, the key contribution of the residues around the binding pocket of MT-5 in binding to the mTOR protein was also investigated from a computational perspective.Copyright © 2023 Elsevier Inc. All rights reserved.