Effect of potent and selective inhibitors of the Grb2 SH2 domain on cell motility

Cell motility has been correlated both with oncogenic invasiveness and meta static potential. The development of selective inhibitors of motility has t hus great potential importance. Grb2 is a SH2/SH3 domain-containing adaptor protein that links growth factor receptor tyrosine kinases to the Ras sign aling pathway, We have developed specific small molecule inhibitors of the Grb2 SH2 domain as potential leads for drug discovery, Synthesis of the inh ibitors and their effects on growth factor-induced growth in cells have bee n reported previously. In the current study, we establish that these inhibi tors inhibit hepatocyte growth factor/scatter factor-induced A431 and Madin -Darby canine kidney cell motility and various cell motility-related events , including epidermal growth factor-induced ruffling of A431 cells and epid ermal growth factor-induced translocation of the small GTPase Rac in these cells. We demonstrate for the first time a direct role for Grb2 in cell mot ility and indicate a new avenue for cancer therapeutics.