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In order to interrupt the signaling induced by the oncogenic HER2 protein involved in breast cancer, we decided to inhibit protein-protein interactions at the level of the SH3 (Src Homology 3) domains of Grb2 protein. Grb2 is a small adaptor, constituted by one SH2 surrounded by two SH3 domains, involved in Ras-dependent pathway. Through its SH2 domain, Grb2 interacts with EGFR and/or HER2. Via its SH3 domains it interacts with proline-rich motives of Sos, the exchange factor of Ras. On the basis of Grb2 structural data, we have designed and synthesized, through solid phase peptide synthesis, different inhibitors binding both SH3 domains of the protein. One of the optimized ligands was conjugated with penetratin to enter the cells and was called “peptidimer”. The design, synthesis and pharmacological tests of this compound are described which validate Grb2 as an anti-tumor target. The peptidimer inhibits cell growth in a clonogenic assay on NIH3T3/HER2 and on SKBr3, a human established cell line over-expressing HER2. Interestingly, in association with docetaxel (Taxotere®), the peptidimer shows a synergistic effect in these experiments. Peptidimer/docetaxel combined treatment gives a similar effect as docetaxel treatment alone with one magnitude order lower dose in docetaxel.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]