Mechanism-based design of a protein kinase inhibitor

• Published in: Nature structural & molecular biology Vol. 8; no. 1; pp. 37 - 41
• Main Authors: Hubbard, Stevan R, Cole, Philip A, Parang, Keykavous, Till, Jeffrey H, Ablooglu, Ararat J, Kohanski, Ronald A
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.01.2001
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - metabolism; Animals; Binding Sites; Catalytic Domain; Chickens; Crystallography, X-Ray; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Development strategies; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Hydrogen Bonding; Kinetics; Magnesium - metabolism; Models, Molecular; Peptides - chemistry; Peptides - metabolism; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Receptor, Insulin - antagonists & inhibitors; Receptor, Insulin - chemistry; Receptor, Insulin - metabolism; Substrate Specificity
• DOI: 10.1038/83028
• ISSN: 1072-8368; 1545-9993

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 ATPγS 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.