[Design of new anti-tumor agents interrupting deregulated signaling pathways induced by tyrosine kinase proteins. Inhibition of protein-protein interaction involving Grb2].
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.
Vidal
Michel
M
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.
Liu
Wang Qing
WQ
Gril
Brunile
B
Assayag
Franck
F
Poupon
Marie-France
MF
Garbay
Christiane
C
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
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011505:Protein-Tyrosine Kinases
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.