Identification of acylthiourea derivatives as potent Plk1 PBD inhibitors.
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.
Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Taikangxiang
T
Yun
BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
Tan
T
Qin
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.
Ying
Y
Liu
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.
Luhua
L
Lai
D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006219:Halogens / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013379:Substrate Specificity; D013890:Thiourea / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D006219:Halogens; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013890:Thiourea; D000097869:Polo-Like Kinase 1
Binding affinity; Halogenosulfamoylphenyl acylthiourea; In vitro assay; Polo-box domain; Polo-like kinase 1; Small molecular inhibitor