Comprehensive characterization of the Published Kinase Inhibitor Set
Open accessAbstract
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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GPCRs are important off-targets for kinase inhibitors, ion channel modulators, anti-infectives and other drug-like molecules.
“GPCRs also represent important off-targets for kinase inhibitors62,63, ion channel modulators64, anti-infectives65 and other classes of drug-like molecules53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [62]
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References 58 · Cited by 323
- Authors
- Elkins, J. M., Fedele, V., Szklarz, M., Abdul Azeez, K. R., Salah, E., Mikolajczyk, J., Romanov, S., Sepetov, N., Huang, X.-P., Roth, B. L., Al Haj Zen, A., Fourches, D., Muratov, E., Tropsha, A., Morris, J., Teicher, B. A., Kunkel, M., Polley, E., Lackey, K. E., Atkinson, F. L., Overington, J. P., Bamborough, P., Müller, S., Price, D. J., Willson, T. M., Drewry, D. H., Knapp, S., & Zuercher, W. J.
- Affiliations
- University of Oxford (GB)
- University of North Carolina at Chapel Hill (US)
- Nanosyn (United States) (US)
- National Institutes of Health (US)
- Medical University of South Carolina (US)
- European Bioinformatics Institute (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- GlaxoSmithKline (United States) (US)
- Goethe University Frankfurt (DE)
- Corresponding author
- Drewry, David H
- Knapp, Stefan
- Zuercher, William J
- ORCID
- Elkins, Jonathan M
- Fedele, Vita
- Salah, Eidarus
- Huang, Xi-Ping
- Roth, Bryan L
- Fourches, Denis
- Muratov, Eugene
- Morris, Joel
- Teicher, Beverly A
- Kunkel, Mark
- Polley, Eric
- Atkinson, Francis L
- Overington, John P
- Bamborough, Paul
- Müller, Susanne
- Price, Daniel J
- Willson, Timothy M
- Drewry, David H
- Knapp, Stefan
- Zuercher, William J
- Venue
- Nature Biotechnology
- Published
- 2016-01
- Volume
- 34
- Issue
- 1
- Pages
- 95-103
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W1918079945
- Cited by
- 323
- References
- 58
- Citations by year
- 2026: 18 · 2025: 15 · 2024: 18 · 2023: 31 · 2022: 31 · 2021: 35 · 2020: 39 · 2019: 31 · 2018: 50 · 2017: 35 · 2016: 18 · 2015: 2
- FWCI
- 36.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Biotechnology (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Wellcome Trust (106169/Z/14/Z, 104104, 106169)
- British Heart Foundation (RE/13/1/30181)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- protein kinase inhibitors, ATP-competitive kinase inhibitors, chemical probes, G protein-coupled receptors, tumor cell proliferation, angiogenesis
- MeSH terms
- Glycosylation, Phosphotransferases, Protein Kinase Inhibitors
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