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Comprehensive characterization of the Published Kinase Inhibitor Set

2015; Nature Portfolio; Volume: 34; Issue: 1 Linguagem: Inglês

10.1038/nbt.3374

1546-1696

Jonathan M. Elkins, Vita Fedele, M. Szklarz, K.R. Abdul Azeez, E. Salah, Jowita Mikolajczyk, Sergei Romanov, Nikolai F. Sepetov, Xi‐Ping Huang, Bryan L. Roth, Ayman Al Haj Zen, Denis Fourches, Eugene Muratov, Alex Tropsha, Joel Morris, Beverly A. Teicher, Mark W. Kunkel, Eric C. Polley, Karen Lackey, Francis Atkinson, John P. Overington, Paul Bamborough, Susanne Müller, Daniel J. Price, Timothy M. Willson, David H. Drewry, Stefan Knapp, William J. Zuercher,

Histone Deacetylase Inhibitors Research

A well-characterized library of experimental kinase inhibitors provides leads for targeting the untargeted kinome. 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.