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      Profile of the GSK Published Protein Kinase Inhibitor Set Across ATP-Dependent and-Independent Luciferases: Implications for Reporter-Gene Assays

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          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.

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          Author and article information

          Contributors
          Role: Editor
          Journal
          PLoS One
          PLoS ONE
          plos
          plosone
          PLoS ONE
          Public Library of Science (San Francisco, USA )
          1932-6203
          2013
          7 March 2013
          : 8
          : 3
          Affiliations
          [1 ]National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America
          [2 ]National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America
          [3 ]Department of Chemical Biology, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America
          Albert-Ludwigs-University, Germany
          Author notes

          Competing Interests: William J. Zuercher and David H. Drewry are employees of GlaxoSmithKline and this does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

          Conceived and designed the experiments: JI DSA PD. Performed the experiments: PD RM. Analyzed the data: PD RM RG DSA. Contributed reagents/materials/analysis tools: WJZ DHD RG. Wrote the paper: JI DSA DHD WJZ.

          [¤]

          Current address: Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, United States of America

          Article
          PONE-D-12-39157
          10.1371/journal.pone.0057888
          3591448
          23505445
          a3f70dd0-c157-4434-8f41-f73a7225fbd0

          This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

          Page count
          Pages: 9
          Funding
          This work was supported by the NIH Roadmap for Medical Research (J.I. and D.S.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
          Categories
          Research Article
          Biology
          Molecular Cell Biology
          Signal Transduction
          Signaling Cascades
          Signaling Pathways
          Chemistry
          Medicinal Chemistry
          Synthetic Chemistry
          Heterocycle Structures
          Medicine
          Drugs and Devices
          Drug Research and Development
          Drug Discovery

          Uncategorized

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