title: Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen.
abstract: Using a newly developed competitive binding assay dependent upon the reassembly of a split reporter protein, we have tested the promiscuity of a panel of reported kinase inhibitors against the AGC group. Many non-AGC targeted kinase inhibitors target multiple members of the AGC group. In general, structurally similar inhibitors consistently exhibited activity toward the same target as well as toward closely related kinases. The inhibition data was analyzed to test the predictive value of either using identity scores derived from residues within 6 Å of the active site or identity scores derived from the entire kinase domain. The results suggest that the active site identity in certain cases may be a stronger predictor of inhibitor promiscuity. The overall results provide general guidelines for establishing inhibitor selectivity as well as for the future design of inhibitors that either target or avoid AGC kinases.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, 1306 East University Boulevard, Tucson, Arizona 85721, United States.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Jester
authors.forename: Alicia
authors.initials: A
authors.lastname: Gaj
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Shomin
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Cox
authors.forename: Indraneel
authors.initials: I
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D020134:Catalytic Domain; D002474:Cell-Free System; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016208:Databases, Factual; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D008156:Luciferases; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; D011493:Protein Kinase C