Structure-based design of a non-peptidic antagonist of the SH2 domain of GRB2

The structure-based design and synthesis of a completely non-peptidic, micromolar antagonist of the SH2 domain of Grb2 is presented. The compound mimics the two main pharmacophores of the natural ligand, the phenylphosphate of the phosphotyrosine residue and the β-carboxamide of the X+2 asparagine, which are linked by a rigid aromatic spacer.