title: Profile of the GSK published protein kinase inhibitor set across ATP-dependent and-independent luciferases: implications for reporter-gene assays.
abstract: A library of 367 protein kinase inhibitors, the GSK Published Kinase Inhibitor Set (PKIS), which has been annotated for protein kinase family activity and is available for public screening efforts, was assayed against the commonly used luciferase reporter enzymes from the firefly, Photinus pyralis (FLuc) and marine sea pansy, Renilla reniformis (RLuc). A total of 22 compounds (∼6% of the library) were found to inhibit FLuc with 10 compounds showing potencies ≤1 µM. Only two compounds were found to inhibit RLuc, and these showed relatively weak potency values (∼10 µM). An inhibitor series of the VEGFR2/TIE2 protein kinase family containing either an aryl oxazole or benzimidazole-urea core illustrate the different structure activity relationship profiles FLuc inhibitors can display for kinase inhibitor chemotypes. Several FLuc inhibitors were broadly active toward the tyrosine kinase and CDK families. These data should aid in interpreting the results derived from screens employing the GSK PKIS in cell-based assays using the FLuc reporter. The study also underscores the general need for strategies such as the use of orthogonal reporters to identify kinase or non-kinase mediated cellular responses.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Dranchak
authors.forename: Ryan
authors.initials: R
authors.lastname: MacArthur
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Guha
authors.forename: William J
authors.initials: WJ
authors.lastname: Zuercher
authors.forename: David H
authors.initials: DH
authors.lastname: Drewry
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Auld
authors.forename: James
authors.initials: J
authors.lastname: Inglese
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D016208:Databases, Factual; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays; D007700:Kinetics; D008156:Luciferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate; D008156:Luciferases