Potent Grb2-SH2 antagonists containing asparagine mimetics

Abstract

Grb2 induces a variety of biol. events including the activation of the Ras-Raf-MEK-MAP kinase signal transduction pathway. Compds. able to specifically block the phys. 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. A strategy in the identification of a suitable replacement for asparagine in Grb2-SH2 antagonists, is briefly highlighted. Asparagine is the residue that dets. specificity for Grb2-SH2 and it has always been present in previously described inhibitors of the above SH2 domain. Structural information has been exploited to identify-2-amino-cyclohex-3-enecarboxylic acid amide as a suitable replacement for asparagine in Grb2-SH2 antagonists. As shown by x-ray crystallog., this cyclic ��-amino acid mimics the intermol. hydrogen bond interactions of asparagine in full agreement with the authors' structure-based design and without loss of inhibitory activity. Data obtained with other sequences seem to indicate that the double bond of rac,cis-2-(9-fluorenylmethoxycarbonylamino)-cyclohex-3-ene carboxylic acid can be removed without affecting the inhibitory activities of Grb2-SH2 antagonists. [on SciFinder(R)]