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Small molecule binding at the Src SH2 domain A variety of proteins involved in signal transduction contain non-catalytic Src homology-2 (SH2) domains that function as mediators of intracellular protein-protein interactions. These SH2 domains (~100 amino acids in size) bind pTyr-containing proteins and peptides in a sequence dependent manner, which provides on a cellular level the basis for differentiation of the phosphorylation/dephosphorylation events surrounding a multitude of signalling pathways. This intricate role of SH2 domains in cell function coupled with the postulated involvement of the nonreceptor tyrosine kinase Src in various disease states, such as cancer and osteoporosis, provides an impetus to develop Src SH2-binding small molecules as therapeutic modulators of the aberrant signalling activity associated with these diseases. A solid-phase parallel approach in combination with molecular modelling was used to guide the design and synthesis of library of Src SH2 domain inhibitors (Structure-based design and solid-phase parallel synthesis of phosphorylated nonpeptides to explore hydrophobic binding at the Src SH2 domain, C. A. Metcalf III et. al., J. Comb. Chem., 2, (2000), 305-313). A library of individual compounds was synthesised on Rink amide AM resin. One of the most potent and selective compounds identified was (i) which bound to Src SH2 with an IC 50 of 900 nM. This approach has demonstrated the successful marrying of solid-phase parallel synthesis and structure-based methods to explore binding of small molecules to the Src SH2 domain with a series of phosphorylated nonpeptides. These techniques may again prove useful in designing and synthesising future libraries of novel Src SH2 inhibitors which seek to address cell potency and selectivity issues.
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