Identification of acylthiourea derivatives as potent Plk1 PBD inhibitors

Taikangxiang Yun; Tan Qin; Ying Liu; Luhua Lai

doi:10.1016/j.ejmech.2016.08.043

Identification of acylthiourea derivatives as potent Plk1 PBD inhibitors

Eur J Med Chem. 2016 Nov 29:124:229-236. doi: 10.1016/j.ejmech.2016.08.043. Epub 2016 Aug 22.

Authors

Taikangxiang Yun¹, Tan Qin², Ying Liu³, Luhua Lai⁴

Affiliations

¹ Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
² BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
³ Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. Electronic address: liuying@pku.edu.cn.
⁴ Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: lhlai@pku.edu.cn.

PMID: 27592392
DOI: 10.1016/j.ejmech.2016.08.043

Abstract

Thiourea derivatives have drawn much attention for their latent capacities of biological activities. In this study, we designed acylthiourea compounds as polo-like kinase 1 (Plk1) polo-box domain (PBD) inhibitors. A series of acylthiourea derivatives without pan assay interference structure (PAINS) were synthesized. Four compounds with halogen substituents exhibited binding affinities to Plk1 PBD in low micromole range. The most potent compound (3v) showed selectivity over other subtypes of Plk PBDs and inhibited the kinase activity of full-length Plk1.

Keywords: Binding affinity; Halogenosulfamoylphenyl acylthiourea; In vitro assay; Polo-box domain; Polo-like kinase 1; Small molecular inhibitor.

MeSH terms

Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry*
Cell Cycle Proteins / metabolism
Cell Proliferation / drug effects
Drug Evaluation, Preclinical
Halogens / chemistry
HeLa Cells
Humans
Molecular Docking Simulation
Polo-Like Kinase 1
Protein Domains
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry*
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / chemistry*
Proto-Oncogene Proteins / metabolism
Substrate Specificity
Thiourea / chemistry*
Thiourea / metabolism
Thiourea / pharmacology*

Substances

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