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).
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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.
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S.R. and N.S. are current employees of Nanosyn, Inc. J.P.O. is a current employee of Stratified Medical Ltd.
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Elkins, J., Fedele, V., Szklarz, M. et al. Comprehensive characterization of the Published Kinase Inhibitor Set. Nat Biotechnol 34, 95–103 (2016). https://doi.org/10.1038/nbt.3374
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DOI: https://doi.org/10.1038/nbt.3374
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