2. Academic Validation
  3. Comprehensive characterization of the Published Kinase Inhibitor Set

Comprehensive characterization of the Published Kinase Inhibitor Set

  • Nat Biotechnol. 2016 Jan;34(1):95-103. doi: 10.1038/nbt.3374.
Jonathan M Elkins 1,  Vita Fedele 1,  Marta Szklarz 1,  Kamal R Abdul Azeez 1,  Eidarus Salah 1,  Jowita Mikolajczyk 2,  Sergei Romanov 2,  Nikolai Sepetov 2,  Xi-Ping Huang 3,  Bryan L Roth 3,  Ayman Al Haj Zen 4,  Denis Fourches 5,  Eugene Muratov 5,  Alex Tropsha 5,  Joel Morris 6,  Beverly A Teicher 6,  Mark Kunkel 6,  Eric Polley 6,  Karen E Lackey 7,  Francis L Atkinson 8,  John P Overington 8,  Paul Bamborough 9,  Susanne Müller 1,  Daniel J Price 10,  Timothy M Willson 10,  David H Drewry 10,  Stefan Knapp 1 11 12,  William J Zuercher 10
Affiliations

Affiliations

  • 1 Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
  • 2 Nanosyn, Inc., Santa Clara, California, USA.
  • 3 The National Institute of Mental Health Psychoactive Active Drug Screening Program, (NIMH PDSP), Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
  • 4 British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • 5 Laboratory for Molecular Modeling Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 6 Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, USA.
  • 7 Medical University of South Carolina, Charleston, South Carolina, USA.
  • 8 European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
  • 9 Chemical Sciences, GlaxoSmithKline, Stevenage, UK.
  • 10 Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
  • 11 Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
  • 12 Buchmann Institute for Molecular Life Sciences (BMLS), Frankfurt am Main, Germany.
PMID: 26501955 DOI: 10.1038/nbt.3374
Abstract

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of Cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate Cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.

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