Exploiting substrate recognition for selective inhibition of protein kinases

Protein kinases have been identified as potential drug discovery targets in many human diseases. Intensive efforts have been made in developing protein kinases inhibitors but a major challenge is achieving specificity. Exploiting regulatory elements outside the ATP binding pocket, such as the substrate binding site, may provide an alternative that allows generation of competitive inhibitors with improved selectivity. In-depth understanding of substrate recognition by protein kinase is thus essential for design and refinement of competitive inhibitors. Here we described strategies for specifically targeting protein kinases, and highlight our current progress in the development of a substrate competitive inhibitor for glycogen synthase kinase-3 (GSK-3).