Structure-based design of compounds inhibiting Grb2-SH2 mediated protein-protein interactions in signal transduction pathways

Receptor protein tyrosine kinases are usually activated upon binding their growth factors, or other suitable ligands, to their extracellular domains. These activated receptors initiate cytoplasmic signalling cascades which, w hen aberrant, can result in different disease states, such as oncogenic tra nsformation. Many receptor protein tyrosine kinases use Src homology 2 doma ins (SH2) to couple growth factor activation with intracellular signalling pathways to mediate cell control and other biological events. The character ization of the components involved in these signal transduction pathways ha s resulted in the identification of new attractive targets for therapeutic intervention. Such is the case for the protein-protein interactions involvi ng the SH2 domain of growth factor receptor bound protein 2 (Grb2). Agents that specifically disrupt Grb2-SH2 binding interactions involved in aberran t signalling could potentially shut down these oncogenic pathways and thus block human malignancies. This paper reviews the structural characteristics of the Grb2-SH2 domain an d the approaches which have been used to identify antagonists of the Grb2-S H2 domain. Examples have been selected from our own research to illustrate how the unique structural features of the ligand-bound Grb2-SH2 have been e xploited to design potent and selective Grb2-SH2 antagonists.