Development of Src tyrosine kinase substrate binding site inhibitors.

The majority of marketed drugs or drug candidates that target protein kinases and which are currently undergoing clinical trials are ATP binding site inhibitors. The process of designing a selective inhibitor as an ATP mimic is challenging, mainly because of the presence of a large number of protein kinases that show a conserved ATP binding site. The substrate binding site of protein kinases is less conserved than the ATP binding site, and provides an opportunity to design valuable chemical tools which can be utilized to understand the catalytic mechanism of the enzyme, or to develop inhibitors with enhanced specificity. In this review, the latest developments of four classes of substrate binding site inhibitors of Src tyrosine kinase are discussed.