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.
Department of Pharmacology and Molecular Sciences, 317 Hunterian, School of Medicine, 725 North Wolfe Street, Johns Hopkins University, Baltimore, Maryland 21205-2185, USA.
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D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051380:GRB2 Adaptor Protein; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051746:ZAP-70 Protein-Tyrosine Kinase; D018909:src Homology Domains / Q000187:drug effects*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D007166:Immunosuppressive Agents; D011506:Proteins; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D019061:src-Family Kinases