期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 144, 期 -, 页码 517-528出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.12.046
关键词
Apoptosis; Autophagy; Breast cancer; EEF2K; Kinase inhibitor; PLK1
资金
- National Natural Science Foundation of China [21772131, 21472130]
- Fundamental Research Funds of Science & Technology Department of Sichuan Province [2017JY0123]
- Fundamental Research Funds for the Central Universities
- Distinguished Young Scholars of Sichuan University [2015SCU04A13]
Both PLK1 and EEF2K are serine/threonine kinases that play important roles in the proliferation and programmed cell death of various types of cancer. They are highly expressed in breast cancer tissues. Based on the multiple-complexes generated pharmacophore models of PLK1 and homology models of EEF2K, the integrated virtual screening is performed to discover novel PLK1/EEF2K dual inhibitors. The top ten hit compounds are selected and tested in vitro, and five of them display PLK1 and EEF2K inhibition in vitro. Based on the docking modes of the most potent hit compound, a series of derivatives are synthesized, characterized and biological assayed on the PLK1, EEF2K as well as breast cancer cell proliferation models. Compound 18i with satisfied inhibitory potency are shifted to molecular mechanism studies contained molecular dynamics simulations, cell cycles, apoptosis and autophagy assays. Our results suggested that these novel PLK1/EEF2K dual inhibitors can be used as lead compounds for further development breast cancer chemotherapy. (C) 2017 Elsevier Masson SAS. All rights reserved.
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