Bivalent Inhibitors of Protein Kinases

Protein kinases are a diverse enzyme family that mediate intracellular protein phosphorylation. Despite widespread interest in this important enzyme family, the function of most kinases is still not well understood and the role of specific kinases in the etiology of disease is unclear. For this reason, reagents that allow the function of specific kinases to be dissected are of great utility. Selective inhibitors that block the catalytic activity of protein kinases have emerged as useful tools for this purpose. We have developed a new strategy for generating bivalent inhibitors of protein kinases. These chimeric inhibitors consist of a synthetic, ATP‐competitive inhibitor that is covalently tethered to a genetically‐encoded protein that contains a peptide ligand for a second binding domain of the kinase being targeted. We have demonstrated the utility of this method by generating several protein‐small molecule conjugates that simultaneously target the SH1 and SH3 domains of the tyrosine kinases SRC and ABL. Further extension of this methodology to the protein kinases p38, Pim1, and EGFR will be presented. In all examples the use of secondary binding interactions to gain selectivity will be highlighted.