Format

Send to

Choose Destination
Eur J Med Chem. 2018 Jan 20;144:517-528. doi: 10.1016/j.ejmech.2017.12.046. Epub 2017 Dec 14.

Design, synthesis, and biological evaluation of polo-like kinase 1/eukaryotic elongation factor 2 kinase (PLK1/EEF2K) dual inhibitors for regulating breast cancer cells apoptosis and autophagy.

Author information

1
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Department of Breast Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
2
State Key Laboratory of Biotherapy and Department of Breast Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
3
State Key Laboratory of Biotherapy and Department of Breast Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; School of Pharmacy and Sichuan Province College Key Laboratory of Structure-Specific Small Molecule Drugs, Chengdu Medical College, Chengdu 610500, China. Electronic address: jiangqinglin@cmc.edu.cn.
4
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China. Electronic address: guoli@scu.edu.cn.
5
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Department of Breast Surgery, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Electronic address: hegu@scu.edu.cn.

Abstract

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.

KEYWORDS:

Apoptosis; Autophagy; Breast cancer; EEF2K; Kinase inhibitor; PLK1

PMID:
29288948
DOI:
10.1016/j.ejmech.2017.12.046
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center