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.
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Department of Pharmacology and Molecular Sciences, 317 Hunterian, School of Medicine, 725 North Wolfe Street, Johns Hopkins University, Baltimore, Maryland 21205-2185, USA.
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