Antagonists of the Src homology 2 (SH2) domains of Grb2, Src, Lck and ZAP-70

Sre homology 2 (SH2) domains are protein modules that mediate intracellular protein-protein interactions in signal transduction pathways. The specific association of an SH2 domain with a phosphotyrosine-containing sequence of another protein induces a cascade of molecular interactions that effect a wide range of cellular processes. Alterations in these signaling pathways h ave been associated with the development and progression of a broad range o f pathologies. Because of the regulatory role of SH2 domains in these signa l transduction pathways, specific SH2 domains can be ideal targets for inte rvention with therapeutic agents in many different disease indications (e.g . cancer, osteoporosis, disorders of the immune and cardiovascular systems) . Among the SH2 domains pursued as drug discovery targets in the last few y ears are those of Grb2, Src, Lck and ZAP-70. This review focuses on contrib utions in the design and synthesis of antagonists of these particular SH2 d omains. Specific examples have been selected to illustrate how structure-ba sed design approaches have been used to progress in this area of research.