Mechanism-based design of a protein kinase inhibitor |
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Authors: | Parang K Till J H Ablooglu A J Kohanski R A Hubbard S R Cole P A |
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Institution: | The Johns Hopkins University School of Medicine, Department of Pharmacology Molecular Sciences, Baltimore, Maryland 21205, USA. |
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Abstract: | Protein kinase inhibitors have applications as anticancer therapeutic agents and biological tools in cell signaling. Based on a phosphoryl transfer mechanism involving a dissociative transition state, a potent and selective bisubstrate inhibitor for the insulin receptor tyrosine kinase was synthesized by linking ATPgammaS to a peptide substrate analog via a two-carbon spacer. The compound was a high affinity competitive inhibitor against both nucleotide and peptide substrates and showed a slow off-rate. A crystal structure of this inhibitor bound to the tyrosine kinase domain of the insulin receptor confirmed the key design features inspired by a dissociative transition state, and revealed that the linker takes part in the octahedral coordination of an active site Mg2+. These studies suggest a general strategy for the development of selective protein kinase inhibitors. |
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