title: Tampering with cell division by using small-molecule inhibitors of CDK-CKS protein interactions.
abstract: Cyclin-dependent kinases (CDKs) control many cellular processes and are considered important therapeutic targets. Large collections of inhibitors targeting CDK active sites have been discovered, but their use in chemical biology or drug development has been often hampered by their general lack of specificity. An alternative approach to develop more specific inhibitors is targeting protein interactions involving CDKs. CKS proteins interact with some CDKs and play important roles in cell division. We discovered two small-molecule inhibitors of CDK-CKS interactions. They bind to CDK2, do not inhibit its enzymatic activity, inhibit the proliferation of tumor cell lines, induce an increase in G1 and/or S-phase cell populations, and cause a decrease in CDK2, cyclin A, and p27(Kip1) levels. These molecules should help decipher the complex contributions of CDK-CKS complexes in the regulation of cell division, and they might present an interesting therapeutic potential.
authors.affiliation: UMSR 3151 CNRS, Université Pierre et Marie Curie, Protein Phosphorylation and Human Disease Unit, P2I2group, Station Biologique, Place Georges Teissier, 29680 Roscoff (France).
authors.forename: Amel
authors.initials: A
authors.lastname: Hamdi
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lesnard
authors.forename: Peggy
authors.initials: P
authors.lastname: Suzanne
authors.forename: Thomas
authors.initials: T
authors.lastname: Robert
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
authors.forename: Morgan
authors.initials: M
authors.lastname: Pellerano
authors.forename: Bruno
authors.initials: B
authors.lastname: Didier
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ficko-Blean
authors.forename: Annelise
authors.initials: A
authors.lastname: Lobstein
authors.forename: Marcel
authors.initials: M
authors.lastname: Hibert
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.forename: May C
authors.initials: MC
authors.lastname: Morris
authors.forename: Pierre
authors.initials: P
authors.lastname: Colas
mesh_terms: D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D060066:Protein Interaction Maps / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C093090:CKS1B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019925:Cyclin A; D054852:Small Molecule Libraries; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C083689:CKS2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: cytostatic agents; natural products; protein kinases; protein-protein interactions