Discovery and evaluation of dual CDK1 and CDK2 inhibitors.
In eukaryotic cells, cyclin-dependent kinase (CDK) complexes regulate the temporal progression of cells through the cell cycle. Deregulation in the cell cycle is an essential component in the evolution of cancer. Here, we validate CDK1 and CDK2 as potential therapeutic targets using novel selective small-molecule inhibitors of cyclin B1/CDK1 and cyclin E2/CDK2 enzyme complexes (CDKi). Flow cytometry-based methods were developed to assess intracellular retinoblastoma (Rb) phosphorylation to show inhibition of the CDK pathway. Tumor cells treated with CDK inhibitors showed an overall decrease in cell proliferation, accumulation of cells in G1 and G2, and apoptosis in a cell line-specific manner. Although CDK inhibitors activate p53, the inhibitors were equipotent in arresting the cell cycle in isogenic breast and colon tumor cells lacking p53, suggesting the response is independent of p53. In vivo, the CDK inhibitors prevented the growth of colon and prostate tumors, blocked proliferation of tumor cells, and inhibited Rb phosphorylation. The discovery and evaluation of novel potent and selective CDK1 and CDK2 inhibitors will help delineate the role that CDK complexes play in regulating tumorigenesis.
Payton
Marc
M
Department of Cancer Biology, Amgen, Inc., Thousand Oaks, California 91320-1789, USA. mpayton@amgen.com
Chung
Grace
G
Yakowec
Peter
P
Wong
Andrew
A
Powers
Dave
D
Xiong
Ling
L
Zhang
Nancy
N
Leal
Juan
J
Bush
Tammy L
TL
Santora
Vincent
V
Askew
Ben
B
Tasker
Andrew
A
Radinsky
Robert
R
Kendall
Richard
R
Coats
Steve
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D056744:Cyclin B1; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D019927:Cyclin E; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2