Abstract
Polo-like kinases (Plks) have several functions in mitotic progression and are upregulated in many tumor types. Small-molecule Plk inhibitors would be valuable as tools for studying Plk biology and for developing antitumor agents. Guided by homology modeling of the Plk1 kinase domain, we have discovered a chemical series that shows potent and selective Plk1 inhibition. The effects of one such optimized benzthiazole N-oxide, cyclapolin 1 (1), on purified centrosomes indicate that Plks are required to generate MPM2 epitopes, recruit gamma-tubulin and enable nucleation of microtubules. The compound can also promote loss of centrosome integrity and microtubule nucleating ability apparently through increased accessibility of protein phosphatases. We show that treatment of living S2 cells with cyclapolin 1 leads to collapsed spindles, in contrast to the metaphase-arrested bipolar spindles observed after RNAi. This different response to protein depletion and protein inhibition may have significance in the development of antitumor agents.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzothiazoles / chemistry
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Benzothiazoles / pharmacology*
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Binding Sites
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / physiology
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Cell Line
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Centrosome / drug effects
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Centrosome / metabolism
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Cyclic N-Oxides / chemistry
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Cyclic N-Oxides / pharmacology*
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Drosophila melanogaster / cytology
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Drosophila melanogaster / drug effects*
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HeLa Cells
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Humans
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Microtubules / drug effects
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Microtubules / metabolism
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Models, Molecular
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Molecular Structure
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Polo-Like Kinase 1
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / physiology
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / physiology
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Spindle Apparatus / drug effects*
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Spindle Apparatus / physiology
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Stereoisomerism
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Structure-Activity Relationship
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Time Factors
Substances
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4-(trifluorosulfanyl)-6-nitrobenzothiazole-2-carboxamide N-oxide
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Benzothiazoles
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Cell Cycle Proteins
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Cyclic N-Oxides
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Protein Serine-Threonine Kinases
Associated data
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PubChem-Substance/14717159
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PubChem-Substance/14717160
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PubChem-Substance/14717161
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PubChem-Substance/14717162
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PubChem-Substance/14717163
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PubChem-Substance/14717164
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PubChem-Substance/14717165
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PubChem-Substance/14717166
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PubChem-Substance/14717167
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PubChem-Substance/14717168