title: Designed inhibitor for nuclear localization signal of polo-like kinase 1 induces mitotic arrest.
abstract: Polo-like kinase 1 (Plk1), a member of polo-like kinase family, regulates multiple essential steps of the cell cycle progression. Plk1 is overexpressed in multiple cancer cell lines and considered to be a prime anticancer target. Plk1 accumulates in the nucleus during S and G2 phases by its bipartite nuclear localization signal (NLS) sequence, which is crucial for Plk1 regulation during normal cell cycle progression. Here, through combined computational and experimental studies, we identified compound D110, which inhibits Plk1 kinase activity with an IC50of 85 nm and blocks the nuclear localization of Plk1 during S and G2 phases. D110-treated cancer cells were arrested at mitosis with monopolar spindle, indicating the inhibition of the Plk1 kinase activity in cell. As D110 interacts with both the ATP site and the NLS in Plk1, it demonstrates good selectivity toward Plk2 and Plk3. The strategy of simultaneously inhibiting kinase activity and its subcellular translocations offers a novel approach for selective kinase inhibitor design.
authors.affiliation: Center for Quantitative Biology, Peking University, Beijing, China.
authors.forename: Fangjin
authors.initials: F
authors.lastname: Chen
authors.affiliation: The Ministry of Education Key Laboratory of Cell Proliferation and Differentiation and the State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhuo
authors.affiliation: BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
authors.forename: Tan
authors.initials: T
authors.lastname: Qin
authors.affiliation: The Ministry of Education Key Laboratory of Cell Proliferation and Differentiation and the State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Guo
authors.affiliation: The Ministry of Education Key Laboratory of Cell Proliferation and Differentiation and the State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Chuanmao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Center for Quantitative Biology, Peking University, Beijing, China.|BNLMS, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D015195:Drug Design; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects; D062105:Molecular Docking Simulation; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012545:Schiff Bases / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D053778:Thiazolidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012545:Schiff Bases; D053778:Thiazolidines; D000097869:Polo-Like Kinase 1; C000618214:D110 compound
keywords: Plk1 inhibitor; anticancer; mitotic arrest; nuclear localization signal; polo-like kinase 1