Martin Zeller

Potent Grb2-SH2 antagonists containing asparagine mimetics

Grb2 induces a variety of biological events including the activation of the Ras-Raf-MEKMAP kinase signal transduction pathway. Compounds able to specifically block the physical interactions involving the SH2 domain of Grb2 could potentially shut-down the above signal transduction pathway and present an intervention point for blocking human malignancies. Structure-based design modifications of the minimal recognition motif of Grb2-SH2 have resulted in highly potent and selective antagonist for this SH2 domain (e.g., phosphopeptide 1, Table 1) [1,2]. We briefly highlight herein our strategy in the identification of a suitable replacement for asparagine in Grb2-SH2 antagonists. Asparagine is the residue that determines specificity for Grb2-SH2 and it has always been present in previously described inhibitors of the above SH2 domain.