Identification of novel peptidomimetics targeting the polo-box domain of polo-like kinase 1

Zhiyan Li; Zhenguo Zhang; Huiyong Sun; Lili Xu; Cheng Jiang

doi:10.1016/j.bioorg.2019.103148

Identification of novel peptidomimetics targeting the polo-box domain of polo-like kinase 1

Bioorg Chem. 2019 Oct:91:103148. doi: 10.1016/j.bioorg.2019.103148. Epub 2019 Jul 27.

Authors

Zhiyan Li¹, Zhenguo Zhang¹, Huiyong Sun², Lili Xu³, Cheng Jiang⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
² Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
³ 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. Electronic address: 1620174420@cpu.edu.cn.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jc@cpu.edu.cn.

PMID: 31376784
DOI: 10.1016/j.bioorg.2019.103148

Abstract

A series of new peptidomimetics targeting the polo-box domain (PBD) of polo-like kinase 1 (Plk1) was identified based on the potent and selective pentapeptide Plk1 PBD inhibitor PLHSpT. Unnatural amino acid residues were introduced to the newly designed compound and the N-terminal substituent of the peptidomimetic was investigated. The optimized compound 9 inhibited the Plk1 PBD with IC₅₀ of 0.267 μM and showed almost no inhibition to Plk2 PBD or Plk3 PBD at 100 μM. Biolayer interferometry studies demonstrated that compound 9 showed potent binding affinity to Plk1 with a K_d value of 0.164 μM, while no K_d were detected against Plk2 and Plk3. Compound 9 showed improved stability in rat plasma compared to PLHSpT. Binding mode analysis was performed and in agreement with the observed experimental results. There are only two natural amino acids remained in the chemical structure of 9. This study may provide new information for further research on Plk1 PBD inhibitors.

Keywords: Inhibitors; Plk1 PBD; Polo-box domain; Polo-like kinase 1; Unnatural amino acid.

Publication types

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

MeSH terms

Animals
Cell Cycle Proteins / antagonists & inhibitors*
Peptidomimetics / chemistry
Peptidomimetics / pharmacology*
Plasma / chemistry*
Polo-Like Kinase 1
Protein Binding
Protein Domains
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins / antagonists & inhibitors*
Rats

Substances

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