Comprehensive characterization of the Published Kinase Inhibitor Set.
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.
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Jonathan M
http://orcid.org/0000-0003-2858-8929
JM
Elkins
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Vita
V
Fedele
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Marta
M
Szklarz
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Kamal R
KR
Abdul Azeez
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Eidarus
E
Salah
Nanosyn, Inc., Santa Clara, California, USA.
Jowita
J
Mikolajczyk
Nanosyn, Inc., Santa Clara, California, USA.
Sergei
S
Romanov
Nanosyn, Inc., Santa Clara, California, USA.
Nikolai
N
Sepetov
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
XP
Huang
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.
Bryan L
BL
Roth
British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Ayman
A
Al Haj Zen
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
D
Fourches
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.
Eugene
E
Muratov
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.
Alex
A
Tropsha
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, USA.
Joel
J
Morris
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, USA.
Beverly A
BA
Teicher
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, USA.
Mark
M
Kunkel
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland, USA.
Eric
E
Polley
Medical University of South Carolina, Charleston, South Carolina, USA.
Karen E
KE
Lackey
European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Francis L
FL
Atkinson
European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
John P
http://orcid.org/0000-0002-5859-1064
JP
Overington
Chemical Sciences, GlaxoSmithKline, Stevenage, UK.
Paul
P
Bamborough
Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, Old Road Campus, University of Oxford, Oxford, UK.
Susanne
S
Müller
Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Daniel J
DJ
Price
Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
Timothy M
TM
Willson
Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
David H
DH
Drewry
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.
Stefan
S
Knapp
Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
William J
WJ
Zuercher
D006031:Glycosylation; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D010770:Phosphotransferases