2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffold

Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffold

  • Eur J Med Chem. 2018 Jan 1:143:724-731. doi: 10.1016/j.ejmech.2017.11.058.
Mei-Miao Zhan 1,  Yang Yang 1,  Jinfeng Luo 2,  Xing-Xing Zhang 1,  Xuan Xiao 1,  Shiyu Li 1,  Kai Cheng 1,  Zhouling Xie 1,  Zhengchao Tu 3,  Chenzhong Liao 4
Affiliations

Affiliations

  • 1 School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
  • 2 High Throughput Drug Screening Center, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, PR China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, PR China.
  • 3 High Throughput Drug Screening Center, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, PR China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, PR China. Electronic address: tu_zhengchao@gibh.ac.cn.
  • 4 School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China. Electronic address: czliao@hfut.edu.cn.
PMID: 29220793 DOI: 10.1016/j.ejmech.2017.11.058
Abstract

Polo-like kinase 2 (PLK2) is a potential target for the treatment of Cancer, which displays an important role in tumor cell proliferation and survival. In this report, according to the analysis of critical amino acid residue differences among PLK1, PLK2 and PLK3, and structure-based drug design strategies, two novel series of selective PLK2 inhibitors based on tetrahydropteridin chemical scaffold were designed and synthesized to target two specific residues, Lys86 and Tyr161 of PLK2. All compounds were evaluated for their inhibitory activity against Plk1-Plk3 and the cellular inhibition activity on six different human Cancer cell lines. All efforts led to the identification of the most potent compounds C2 (3.40 nM against PLK2) and C21 (4.88 nM against PLK2) from the first and second series of selective PLK2 inhibitors respectively. Additionally, the selectivity of C21 over PLK1/3 was significantly increased with the selectivity indexes of 12.57 and 910.06. Moreover, most of our compounds exhibited antitumor activity in the nanomolar range in the MTT assay, indicating that our compounds, especially C2 and C21 could be promising PLK2 inhibitors for further Anticancer research.

Keywords

Anticancer; Plk2 inhibitor; Rational drug design; Selectivity; Structure activity relationship.

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