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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Acknowledgements

The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and Wellcome Trust. A.A.H.Z. acknowledges support from the BHF Centre of Research Excellence, Oxford (RE/13/1/30181).

Author information

Author notes

    • Jowita Mikolajczyk
    • , Denis Fourches
    • , John P Overington
    • , Timothy M Willson
    • , David H Drewry
    •  & William J Zuercher

    Present addresses: Novartis Vaccines and Diagnostics, Holly Springs, North Carolina, USA (J. Mikolajczyk); Department of Chemistry, Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina, USA (D.F.); Stratified Medical, London, UK (J.P.O.); Meryx Pharmaceuticals, Chapel Hill, North Carolina, USA (D.H.D.); SGC-UNC, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA (T.M.W., W.J.Z.).

Affiliations

  1. Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.

    • Jonathan M Elkins
    • , Vita Fedele
    • , Marta Szklarz
    • , Kamal R Abdul Azeez
    • , Eidarus Salah
    • , Susanne Müller
    •  & Stefan Knapp
  2. Nanosyn, Inc., Santa Clara, California, USA.

    • Jowita Mikolajczyk
    • , Sergei Romanov
    •  & Nikolai Sepetov
  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.

    • Xi-Ping Huang
    •  & Bryan L Roth
  4. British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

    • Ayman Al Haj Zen
  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.

    • Denis Fourches
    • , Eugene Muratov
    •  & Alex Tropsha
  6. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, USA.

    • Joel Morris
    • , Beverly A Teicher
    • , Mark Kunkel
    •  & Eric Polley
  7. Medical University of South Carolina, Charleston, South Carolina, USA.

    • Karen E Lackey
  8. European Molecular Biology Laboratory–European Bioinformatics Institute (EMBL–EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Francis L Atkinson
    •  & John P Overington
  9. Chemical Sciences, GlaxoSmithKline, Stevenage, UK.

    • Paul Bamborough
  10. Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.

    • Daniel J Price
    • , Timothy M Willson
    • , David H Drewry
    •  & William J Zuercher
  11. Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.

    • Stefan Knapp
  12. Buchmann Institute for Molecular Life Sciences (BMLS), Frankfurt am Main, Germany.

    • Stefan Knapp

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Contributions

K.E.L., J.M.E., A.A.H.Z., J. Morris, S.R., N.S., B.A.T., B.L.R., D.H.D., S.K. and W.J.Z. designed the study. M.S., V.F., K.R.A.A., J.M.E., E.S., A.A.H.Z., J. Mikolajczyk, S.R., N.S. and X.-P.H. performed experiments. J.M.E., A.A.H.Z., J. Morris, B.A.T., A.T., X.-P.H., D.F., E.M., F.L.A., J.P.O., P.B., D.H.D., S.M., S.K., E.P., M.K. and W.J.Z. analyzed data. J.M.E., B.L.R., X.-P.H., A.A.H.Z., P.B., D.H.D., D.J.P., T.M.W., S.K. and W.J.Z. wrote the manuscript.

Competing interests

S.R. and N.S. are current employees of Nanosyn, Inc. J.P.O. is a current employee of Stratified Medical Ltd.

Corresponding authors

Correspondence to David H Drewry or Stefan Knapp or William J Zuercher.

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DOI

https://doi.org/10.1038/nbt.3374

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