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PMID: 26501955 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Comprehensive characterization of the Published Kinase Inhibitor Set.

Nature biotechnology ·Vol. 34 ·No. 1 ·2016-01-00 ·Pages 95-103

Elkins JM, Fedele V, Szklarz M, Abdul Azeez KR, Salah E, Mikolajczyk J, Romanov S, Sepetov N, Huang XP, Roth BL, Al Haj Zen A, Fourches D, Muratov E, Tropsha A, Morris J, Teicher BA, Kunkel M, Polley E, Lackey KE, Atkinson FL, Overington JP, Bamborough P, Müller S, Price DJ, Willson TM, Drewry DH, Knapp S, Zuercher WJ

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.

MeSH Terms
Glycosylation Phosphotransferases/antagonists & inhibitors Protein Kinase Inhibitors/pharmacology
Chemicals
Protein Kinase Inhibitors Phosphotransferases
Authors & Affiliations
28 authors, click to expand affiliations / ORCID
Elkins Jonathan M ORCID
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Fedele Vita
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Szklarz Marta
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Abdul Azeez Kamal R
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Salah Eidarus
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Mikolajczyk Jowita
Nanosyn, Inc., Santa Clara, California, USA.
Romanov Sergei
Nanosyn, Inc., Santa Clara, California, USA.
Sepetov Nikolai
Nanosyn, Inc., Santa Clara, California, USA.
Huang Xi-Ping
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.
Roth Bryan L
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.
Al Haj Zen Ayman
British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Fourches Denis
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.
Muratov Eugene
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.
Tropsha Alex
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.
Morris Joel
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, USA.
Teicher Beverly A
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, USA.
Kunkel Mark
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, USA.
Polley Eric
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, USA.
Lackey Karen E
Medical University of South Carolina, Charleston, South Carolina, USA.
Atkinson Francis L
European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Overington John P ORCID
European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Bamborough Paul
Chemical Sciences, GlaxoSmithKline, Stevenage, UK.
Müller Susanne
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Price Daniel J
Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Willson Timothy M
Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Drewry David H
Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Knapp Stefan
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK. | Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany. | Buchmann Institute for Molecular Life Sciences (BMLS), Frankfurt am Main, Germany.
Zuercher William J
Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
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Article Info
Journal
Nature biotechnology
Abbr.
Nat Biotechnol
ISSN
1546-1696
DOI
10.1038/nbt.3374
Published
2016-01-00
Epub
2015-00-26
Pages
95-103
Language
English
Region
United States
NLM ID
9604648
Subset
IM
Grants
Wellcome Trust · 104104 · United Kingdom
Wellcome Trust · 106169 · United Kingdom
British Heart Foundation · RE/13/1/30181 · United Kingdom
External Links
PubMed source DOI: 10.1038/nbt.3374 View journal details
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