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 G(2)/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.
Vassilev
Lyubomir T
LT
Departments of Discovery Oncology and Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA. lyubomir.vassilev@roche.com
Tovar
Christian
C
Chen
Shaoqing
S
Knezevic
Dejan
D
Zhao
Xiaolan
X
Sun
Hongmao
H
Heimbrook
David C
DC
Chen
Li
L
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000502:physiology*; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D011804:Quinolines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D011804:Quinolines; C512984:RO 3306; D013844:Thiazoles; D016203:CDC2 Protein Kinase