title: Mechanism-based design of a protein kinase inhibitor.
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.
authors.affiliation: The Johns Hopkins University School of Medicine, Department of Pharmacology Molecular Sciences, Baltimore, Maryland 21205, USA.
authors.forename: K
authors.initials: K
authors.lastname: Parang
authors.forename: J H
authors.initials: JH
authors.lastname: Till
authors.forename: A J
authors.initials: AJ
authors.lastname: Ablooglu
authors.forename: R A
authors.initials: RA
authors.lastname: Kohanski
authors.forename: S R
authors.initials: SR
authors.lastname: Hubbard
authors.forename: P A
authors.initials: PA
authors.lastname: Cole
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D002645:Chickens; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate; D011972:Receptor, Insulin; D017868:Cyclic AMP-Dependent Protein Kinases; D008274:Magnesium