Inhibitors of Polo-like kinase reveal roles in spindle-pole maintenance.
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.
McInnes
Campbell
C
Cyclacel Ltd., James Lindsay Place, Dundee DD1 5JJ, UK.
Mazumdar
Aveek
A
Mezna
Mokdad
M
Meades
Christopher
C
Midgley
Carol
C
Scaerou
Fred
F
Carpenter
Lee
L
Mackenzie
Mairi
M
Taylor
Paul
P
Walkinshaw
Malcolm
M
Fischer
Peter M
PM
Glover
David
D
D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D002460:Cell Line; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D004331:Drosophila melanogaster / Q000166:cytology / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008941:Spindle Apparatus / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D000097869:Polo-Like Kinase 1
D052160:Benzothiazoles; D018797:Cell Cycle Proteins; D003497:Cyclic N-Oxides; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C515782:4-(trifluorosulfanyl)-6-nitrobenzothiazole-2-carboxamide N-oxide