Structure-based Design of Compounds Inhibiting Grb2-SH2 Mediated Protein-protein Interactions in Signal Transduction Pathways

Abstract

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, when aberrant, can result in different disease states, such as oncogenic transformation. Many receptor protein tyrosine kinases use Src homology 2 domains (SH2) to couple growth factor activation with intracellular signalling pathways to mediate cell control and other biological events. The characterization of the components involved in these signal transduction pathways has resulted in the identification of new attractive targets for therapeutic intervention. Such is the case for the protein-protein interactions involving the SH2 domain of growth factor receptor bound protein 2 (Grb2). Agents that specifically disrupt Grb2-SH2 binding interactions involved in aberrant signalling could potentially shut down these oncogenic pathways and thus block human malignancies. This paper reviews the structural characteristics of the Grb2-SH2 domain and the approaches which have been used to identify antagonists of the Grb2-SH2 domain. Examples have been selected from our own research to illustrate how the unique structural features of the ligand-bound Grb2-SH2 have been exploited to design potent and selective Grb2-SH2 antagonists.

Integrated transcriptomic and proteomic analyses reveal ɑ‐lipoic acid‐regulated cell proliferation via Grb2‐mediated signalling in hepatic cancer cells

“…Hence, dissecting the EGFR 23 or Met 24 pathways activated by ligand binding is relevant to cancer therapeutics. Some antagonists have been found to bind to the Grb2 SH2 domain to block hepatocyte growth factor (HGF)/EGF‐stimulated Grb2 signalling 25, 26. A particularly useful agent should cross the cell membrane and abrogate the signalling axis and its activation, thereby leading to cell apoptosis or even cellular senescence.…”

Protein‐protein interactions as a target for drugs in proteomics

“…Numerous investigations were done in attempt to design the IDs for proteins possessing stable domains, which interact with receptors [114,[133][134][135][136][137][138]. Some proteins act as oligomer complexes, so IDs may prevent formation of the active dimer.…”

Probing the Tyrosine Phosphorylation State in Breast Cancer by Src Homology 2 Domain Binding

“…Despite these difficulties, however, great progress is being made, and in this section we review efforts aimed at developing inhibitors of the Grb2 and Src SH2 domains. Comprehensive reviews of this field are also available [172,[176][177][178][179].…”

“…In this process, each position of the peptide is treated as a "module" which can be manipulated to mimic binding interactions observed in the crystal structure [26,172,176] (Fig. 3A).…”

“…All these substitutions were then combined to generate novel ß-turn mimicking platforms, which were tested for in vitro binding affinity and for potency in cell-based assays [172,176]. One such compound, CGP78850 (Fig.…”