Protein kinase inhibitors have applications as anti-cancer therapeutic agents
and biological tools in cell signalling. Potent and selective bisubstrate inhibitors
for the insulin receptor tyrosine kinase are based on a phosphoryl transfer mechanism
involving a dissociative transition state. One such inhibitor is synthesized by
linking ATPS to a peptide substrate analog via a two-carbon spacer. The
compound is a high-affinity competitive inhibitor against both nucleotide and peptide
substrate and shows a slow off-rate. A crystal structure of this inhibitor bound
to the tyrosine kinase domain of the insulin receptor confirms the key design features
inspired by a dissociative transition state, and reveal that the linker takes part
in the octahedral coordination of an active site Mg2+ ion.