Recent advances in the design and synthesis of SH2 inhibitors of Src Grb2 and ZAP-70

A perspective is offered on the recent development of Src-homology 2 (SH2) antagonists of Src, Grb2 and ZAP-70. Inhibiting Src SH2 is believed to be a potentially attractive way of regulating bone resorption, Grb2 SH2 has been shown to be an important component of the mitogenic ras pathway; and thus might be of utility in cancer research. ZAP-70 is a tyrosine kinase that is expressed solely in T-cells and natural killer cells. Since inhibition of the tandem SH2 domains of ZAP-70 has been shown to block T-cell proliferation, antagonists for this particular protein could have implications in immune suppression. The emphasis of the article is placed on the structure-based design, synthesis and biological activity of a number of newly reported SH2 antagonists in each of the three areas.