Johns Hopkins University

Mount Sinai School of Medicine

Keykavous Parang

Philip A Cole

Ararat Abloogu

Aliya Courtney

Ronald A Kohanski

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 ATP&#x3b3;S 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 Mgion.

Growing community of inventors

Narragansett, RI, United States of America

Keykavous Parang