Identification of novel and selective non-peptide inhibitors targeting the polo-box domain of polo-like kinase 1

Yanhong Chen; Zhiyan Li; Yu Liu; Tongyuan Lin; Huiyong Sun; Dasong Yang; Cheng Jiang

doi:10.1016/j.bioorg.2018.08.030

Identification of novel and selective non-peptide inhibitors targeting the polo-box domain of polo-like kinase 1

Bioorg Chem. 2018 Dec:81:278-288. doi: 10.1016/j.bioorg.2018.08.030. Epub 2018 Aug 23.

Authors

Yanhong Chen¹, Zhiyan Li¹, Yu Liu¹, Tongyuan Lin², Huiyong Sun³, Dasong Yang⁴, Cheng Jiang⁵

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
² Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yangds@cpu.edu.cn.
⁵ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jc@cpu.edu.cn.

PMID: 30170276
DOI: 10.1016/j.bioorg.2018.08.030

Abstract

A series of non-peptide inhibitors targeting the polo-box domain (PBD) of polo-like kinase 1 (Plk1) was designed based on the potent and selective minimal tripeptide Plk1 PBD inhibitor. Seven compounds were designed, synthesized and evaluated for fluorescence polarization (FP) assay. The most promising compound 10 bound to Plk1 PBD with IC₅₀ of 3.37 μM and had no binding to Plk2 PBD or Plk3 PBD at 100 μM. Molecular docking study was performed and possible binding mode was proposed. MM/GBSA binding free energy calculation were in agreement with the observed experimental results. These novel non-peptide selective Plk1 PBD inhibitors provided new lead compounds for further optimization.

Keywords: Inhibitors; Molecular docking; Non-peptide; Polo like kinase 1; Polo-box domain.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry
Humans
Molecular Docking Simulation
Organophosphonates / chemical synthesis
Organophosphonates / chemistry*
Polo-Like Kinase 1
Protein Domains
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / chemistry
Triazoles / chemical synthesis
Triazoles / chemistry*

Substances

Cell Cycle Proteins
Organophosphonates
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Triazoles
Protein Serine-Threonine Kinases