Inhibition of polo-like kinase 1 by blocking polo-box domain-dependent protein-protein interactions.
The serine/threonine kinase Polo-like kinase 1 (Plk1) is overexpressed in many types of human cancers, and has been implicated as an adverse prognostic marker for cancer patients. Plk1 localizes to its intracellular anchoring sites via its polo-box domain (PBD). Here we show that Plk1 can be inhibited by small molecules which interfere with its intracellular localization by inhibiting the function of the PBD. We report the natural product thymoquinone and, especially, the synthetic thymoquinone derivative Poloxin as inhibitors of the Plk1 PBD. Both compounds inhibit the function of the Plk1 PBD in vitro, and cause Plk1 mislocalization, chromosome congression defects, mitotic arrest, and apoptosis in HeLa cells. Our data validate the Plk1 PBD as an anticancer target and provide a rationale for developing thymoquinone derivatives as anticancer drugs.
Reindl
Wolfgang
W
Department of Molecular Biology, Max Planck Institute of Biochemistry and Munich Center for Integrated Protein Science (CiPS(M)), Martinsried, Germany.
Yuan
Juping
J
Krämer
Andrea
A
Strebhardt
Klaus
K
Berg
Thorsten
T
D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology*; D000097869:Polo-Like Kinase 1
D001565:Benzoates; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011809:Quinones; D000097869:Polo-Like Kinase 1; C569433:poloxin