title: Identification of green tea catechins as potent inhibitors of the polo-box domain of polo-like kinase 1.
abstract: Polo-like kinase 1 (PLK1) plays crucial functions in multiple stages of mitosis and is considered to be a potential drug target for cancer therapy. The functions of PLK1 are mediated by its N-terminal kinase domain and C-terminal polo-box domain (PBD). Most inhibitors targeting the kinase domain of PLK1 have a selectivity issue because of a high degree of structural conservation within kinase domains of all protein kinases. Here, we combined virtual and experimental screenings to identify green tea catechins as potent inhibitors of the PLK1 PBD. Initially, (-)-epigallocatechin, one of the main components of green tea polyphenols, was found to significantly block the binding of fluorescein-labeled phosphopeptide to the PBD at a concentration of 10 μm. Next, additional catechins were evaluated for their dose-dependent inhibition of the PBD and preliminary structure-activity relationships were derived. Cellular analysis further showed that catechins interfere with the proper subcellular localization of PLK1, lead to cell-cycle arrest in the S and G2M phases, and induce growth inhibition of several human cancer cell types, such as breast adenocarcinoma (MCF7), lung adenocarcinoma (A549), and cervical adenocarcinoma (HeLa). Our data provides new insight into understanding the anticancer activities of green tea catechins.
authors.affiliation: Key Laboratory of Chemical Genomics, School of Chemical Biology & Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055 (China).
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Shan
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Shi
authors.forename: Junmin
authors.initials: J
authors.lastname: Quan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001665:Binding Sites; D002392:Catechin / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D010748:Phosphopeptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013662:Tea / Q000737:chemistry* / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D002392:Catechin; D018797:Cell Cycle Proteins; D016650:Fluorescein-5-isothiocyanate; D010748:Phosphopeptides; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013662:Tea; D000097869:Polo-Like Kinase 1
keywords: cancer; catechins; inhibitors; natural products; polo-box domain; polo-like kinase 1; screening