title: [Design of new anti-tumor agents interrupting deregulated signaling pathways induced by tyrosine kinase proteins. Inhibition of protein-protein interaction involving Grb2].
abstract: Cellular signaling pathways induced by growth-factor receptors are frequently deregulated in cancer. Anti-tumor agents that inhibit their enzymatic tyrosine kinase activity have been designed and are now used in human chemotherapy. We propose here an alternative way to interrupt over-expressed signaling by inhibiting protein-protein interactions that involve either the over-expressed proteins or proteins located downstream. The adaptor protein Grb2 over-expressed in connection with HER2/ErbB2/neu in Ras signaling pathway was chosen as a target. Peptides with very high affinity for Grb2 were rationally designed from structural data. Their capacity to interrupt the signaling pathway, their anti-proliferative activity as well as their potential anti-tumor properties are described.
authors.affiliation: UFR Biomédicale des Saints Pères, Laboratoire de Pharmacochimie Moléculaire et Cellulaire, FRE 2718 CNRS, U648 INSERM, 45, rue des Saints-Pères, 75270 Paris Cedex 06.
authors.forename: Michel
authors.initials: M
authors.lastname: Vidal
authors.forename: Wang Qing
authors.initials: WQ
authors.lastname: Liu
authors.forename: Brunile
authors.initials: B
authors.lastname: Gril
authors.forename: Franck
authors.initials: F
authors.lastname: Assayag
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Poupon
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000737:chemistry; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D051380:GRB2 Adaptor Protein; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011505:Protein-Tyrosine Kinases
vernacular_title: Nouvelle approche thérapeutique du cancer. Interruption des voies de signalisation dérégulées par inhibition des interactions inter-protéiques: exemple de la protéine Grb2 dans la signalisation induite par les protéines à activité tyrosine kinase.