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激酶mTOR是PI3K-AKT信号通路的关键组成部分,该激酶在宫颈癌细胞中被高度激活.本文运用基于结构的药物发现等手段发现了一系列mTOR激酶抑制剂并对其进行生物学评价,发现其可发挥有效的抗宫颈癌作用.酶活性测定结果显示化合物C3具有潜在的mTOR抑制作用(IC50=1.57 μM).随后利用分子对接和动力学模拟探究并预测mTOR激酶和C3的结合模式,初步探讨了化合物的构效关系.在多种肿瘤细胞系上进行细胞增殖活性实验时发现,C3对宫颈癌细胞HeLa表现出较好的增殖抑制活性(IC50=0.38 μM).此外,C3还能浓度依赖性地降低磷酸化核糖体S6 (p-S6)蛋白在HeLa细胞内的表达水平.值得注意的是,C3发挥显著的抗宫颈癌活性很有可能是mTOR通路和其他细胞内通路的共同作用.本研究表明C3可进一步开发为宫颈癌的治疗药物.“,”The mammalian target of rapamycin (mTOR) is a critical component of the PI3K-AKT signaling pathway.It is highly activated in cervical cancer,which continues to pose an important clinical challenge with an urgent need for new and improved therapeutic approaches.Herein,we describe the structure-based drug discovery and biological evaluation of a series of mTOR kinase inhibitors as potential anti-cervical cancer agents.The results of enzymatic activity assays supported C3 as a potential mTOR inhibitor,which exhibited high inhibitory activity with an IC50 of 1.57 μM.Molecular docking and dynamics simulation were conducted to predict the binding patterns,suggesting relationships between structure and activity.The anti-proliferative assay against diverse cancer cell lines was displayed subsequently,revealing that C3 exhibited significant proliferation inhibition against cervical cancer cell HeLa (IC50 =0.38 μM) compared with other cell lines.Moreover,C3 could effectively reduce the expression of phospho-ribosomal S6 protein (p-S6) in HeLa cells in a dose-dependent manner.Noteworthily,mTOR signaling and other cellular pathways might contribute to the significant effect of C3 against cervical cancer simultaneously.These data indicated that C3 represented a good lead molecule for further development as a therapeutic agent for cervical cancer treatment.