title: Discovery and evaluation of dual CDK1 and CDK2 inhibitors.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Amgen, Inc., Thousand Oaks, California 91320-1789, USA. mpayton@amgen.com
authors.forename: Marc
authors.initials: M
authors.lastname: Payton
authors.forename: Grace
authors.initials: G
authors.lastname: Chung
authors.forename: Peter
authors.initials: P
authors.lastname: Yakowec
authors.forename: Andrew
authors.initials: A
authors.lastname: Wong
authors.forename: Dave
authors.initials: D
authors.lastname: Powers
authors.forename: Ling
authors.initials: L
authors.lastname: Xiong
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Leal
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Bush
authors.forename: Vincent
authors.initials: V
authors.lastname: Santora
authors.forename: Ben
authors.initials: B
authors.lastname: Askew
authors.forename: Andrew
authors.initials: A
authors.lastname: Tasker
authors.forename: Robert
authors.initials: R
authors.lastname: Radinsky
authors.forename: Richard
authors.initials: R
authors.lastname: Kendall
authors.forename: Steve
authors.initials: S
authors.lastname: Coats
mesh_terms: 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
chemical_list: 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