title: Selective cyclin-dependent kinase 2/cyclin A antagonists that differ from ATP site inhibitors block tumor growth.
abstract: A central function of the tumor suppressor retinoblastoma (Rb) is its ability to repress E2F transcriptional activity. Many cancers harbor inactivated Rb and consequently deregulated E2F. RXL peptides inhibit E2F recruitment and phosphorylation by CDK2/cyclin A. Here we report that RXL peptides selectively kill tumor cells with deregulated Rb/cyclin D pathways. We extend these observations to tumor models and demonstrate inhibition of tumor growth in SV40 large T transformed Balb/c 3T3 grafts and in HER2 transgenic tumors. Moreover, our observations reveal that RXL peptide-treated tumors undergo apoptosis. Our results indicate that RXL motif-based inhibitors will provide selective antiproliferative agents with in vivo efficacy in tumors with deregulated Rb/cyclin D pathways.
authors.affiliation: Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Nerissa
authors.initials: N
authors.lastname: Mendoza
authors.forename: Sharon
authors.initials: S
authors.lastname: Fong
authors.forename: Jim
authors.initials: J
authors.lastname: Marsters
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Ralph
authors.initials: R
authors.lastname: Schwall
authors.forename: Dineli
authors.initials: D
authors.lastname: Wickramasinghe
mesh_terms: D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites; D042846:CDC2-CDC28 Kinases; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D019925:Cyclin A / Q000037:antagonists & inhibitors*; D056741:Cyclin D; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000502:physiology; D005260:Female; D018734:Genes, erbB-2 / Q000235:genetics; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D016160:Retinoblastoma Protein / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D019925:Cyclin A; D056741:Cyclin D; D016213:Cyclins; D009842:Oligopeptides; D016160:Retinoblastoma Protein; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases