title: Identification of a novel Polo-like kinase 1 inhibitor that specifically blocks the functions of Polo-Box domain.
abstract: Polo-like kinase 1 (Plk1) is a promising target for cancer therapy due to its essential role in cell division. In addition to a highly conserved kinase domain, Plk1 also contains a Polo-Box domain (PBD), which is essential for Plk1's subcellular localization and mitotic functions. We adopted a fluorescence polarization assay and identified a new Plk1 PBD inhibitor T521 from a small-molecule compound library. T521 specifically inhibits the PBD of Plk1, but not those of Plk2-3. T521 exhibits covalent binding to some lysine residues of Plk1 PBD, which causes significant changes in the secondary structure of Plk1 PBD. Using a cell-based assay, we showed that T521 impedes the interaction between Plk1 and Bub1, a mitotic checkpoint protein. Moreover, HeLa cells treated with T521 exhibited dramatic mitotic defects. Importantly, T521 suppresses the growth of A549 cells in xenograft nude mice. Taken together, we have identified a novel Plk1 inhibitor that specifically disrupts the functions of Plk1 PBD and shows anticancer activity.
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Yunyu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.|Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Yanchang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Si
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005454:Fluorescence Polarization / Q000379:methods; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D051379:Mice; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1
keywords: Polo-Box domain; Polo-like kinase 1 inhibitor; cancer therapy; fluorescence polarization; protein-protein interactions