Selective Small-Molecule Inhibitor Reveals Critical Mitotic Functions of Human CDK1

CDK1 is a nonredundant cyclin-dependent kinase (CDK) with an essential role in mitosis, but its multiple functions still are poorly understood at a molecular level. Here we identify a selective small-molecule inhibitor of CDK1 that reversibly arrests human cells at the G₂/M border of the cell cycle...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-07, Vol.103 (28), p.10660-10665
Main Authors: Vassilev, Lyubomir T., Tovar, Christian, Chen, Shaoqing, Knezevic, Dejan, Zhao, Xiaolan, Sun, Hongmao, Heimbrook, David C., Chen, Li
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - drug effects
Apoptosis - physiology
Biological Sciences
Catalysis
CDC2 Protein Kinase - antagonists & inhibitors
CDC2 Protein Kinase - physiology
Cell cycle
Cell growth
Cell Line, Tumor
Cell lines
Cell Proliferation - drug effects
Chromatin
Cyclin-dependent kinases
Cyclins
Enzyme Inhibitors - pharmacology
Epithelial cells
HCT116 Cells
HeLa Cells
Humans
Interphase
Mitosis
Mitosis - drug effects
Mitosis - physiology
Quinolines - pharmacology
Radiation therapy
Studies
Thiazoles - pharmacology
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Summary:CDK1 is a nonredundant cyclin-dependent kinase (CDK) with an essential role in mitosis, but its multiple functions still are poorly understood at a molecular level. Here we identify a selective small-molecule inhibitor of CDK1 that reversibly arrests human cells at the G₂/M border of the cell cycle and allows for effective cell synchronization in early mitosis. Inhibition of CDK1 during cell division revealed that its activity is necessary and sufficient for maintaining the mitotic state of the cells, preventing replication origin licensing and premature cytokinesis. Although CDK1 inhibition for up to 24 h is well tolerated, longer exposure to the inhibitor induces apoptosis in tumor cells, suggesting that selective CDK1 inhibitors may have utility in cancer therapy.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0600447103