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

Zhaoping Pan; Yujuan Chen; Jingyan Liu; Qinglin Jiang; Shengyong Yang; Li Guo; Gu He

doi:10.1016/j.ejmech.2017.12.046

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

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

Authors

Zhaoping Pan¹, Yujuan Chen², Jingyan Liu², Qinglin Jiang³, Shengyong Yang², Li Guo⁴, Gu He⁵

Affiliations

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.

PMID: 29288948
DOI: 10.1016/j.ejmech.2017.12.046

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Elongation Factor 2 Kinase / antagonists & inhibitors*
Elongation Factor 2 Kinase / metabolism
Female
Humans
Molecular Docking Simulation
Molecular Structure
Polo-Like Kinase 1
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Cell Cycle Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins
EEF2K protein, human
Protein Serine-Threonine Kinases
Elongation Factor 2 Kinase