title: Discovering new mTOR inhibitors for cancer treatment through virtual screening methods and in vitro assays.
abstract: Mammalian target of rapamycin (mTOR) is an attractive target for new anticancer drug development. We recently developed in silico models to distinguish mTOR inhibitors and non-inhibitors. In this study, we developed an integrated strategy for identifying new mTOR inhibitors using cascaded in silico screening models. With this strategy, fifteen new mTOR kinase inhibitors including four compounds with IC50 values below 10 μM were discovered. In particular, compound 17 exhibited potent anticancer activities against four tumor cell lines, including MCF-7, HeLa, MGC-803, and C6, with IC50 values of 1.90, 2.74, 3.50 and 11.05 μM. Furthermore, cellular studies and western blot analyses revealed that 17 induces cell death via apoptosis by targeting both mTORC1 and mTORC2 within cells and arrests the cell cycle of HeLa at the G1/G0-phase. Finally, multi-nanosecond explicit solvent simulations and MM/GBSA analyses were carried out to study the inhibitory mechanisms of 13, 17, and 40 for mTOR. The potent compounds presented here are worthy of further investigation.
authors.affiliation: Research Center for Drug Discovery &Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.|Pre-Incubator for Innovative Drugs &Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Research Center for Drug Discovery &Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Research Center for Drug Discovery &Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Cell Biology, Jinan University, Guangzhou, 510632, China.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Xu
authors.affiliation: Research Center for Drug Discovery &Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Bao
authors.initials: B
authors.lastname: Cheng
authors.affiliation: Research Center for Drug Discovery &Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Research Center for Drug Discovery &Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Immunobiology, Jinan University, Guangzhou, 510632, China.
authors.forename: Xian-Hui
authors.initials: XH
authors.lastname: He
authors.affiliation: Research Center for Drug Discovery &Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases