期刊
SCIENTIFIC REPORTS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep18987
关键词
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资金
- National Natural Science Foundation of China [81502984, 81001372, 81173470]
- National High Technology Research and Development Program of China (863 Program) [2012AA020307]
- China Postdoctoral Science Foundation [2015M572325]
- Fundamental Research Funds for the Central Universities [2015ZM049]
- Guangdong Recruitment Program of Creative Research Groups
- Special Funding Program for the National Supercomputer Center in Guangzhou [2012Y2-00048/2013Y2-00045, 201200000037]
- Major State Basic Research Development Program of China (973 Program) [2010CB833603]
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 mu M 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 mu M. 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 G(1)/G(0)-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.
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