Comprehensive characterization of the Published Kinase Inhibitor Set

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

doi:10.1038/nbt.3374

Comprehensive characterization of the Published Kinase Inhibitor Set

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

240 Citations (Scopus)

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.

Original language	English
Pages (from-to)	95-103
Number of pages	9
Journal	Nature Biotechnology
Volume	34
Issue number	1
DOIs	https://doi.org/10.1038/nbt.3374
Publication status	Published - 1 Jan 2016
Externally published	Yes

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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., ... Zuercher, W. J. (2016). Comprehensive characterization of the Published Kinase Inhibitor Set. Nature Biotechnology, 34(1), 95-103. https://doi.org/10.1038/nbt.3374

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title = "Comprehensive characterization of the Published Kinase Inhibitor Set",

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.",

author = "Elkins, {Jonathan M.} and Vita Fedele and Marta Szklarz and {Abdul Azeez}, {Kamal R.} and Eidarus Salah and Jowita Mikolajczyk and Sergei Romanov and Nikolai Sepetov and Huang, {Xi Ping} and Roth, {Bryan L.} and {Al Haj Zen}, Ayman and Denis Fourches and Eugene Muratov and Alex Tropsha and Joel Morris and Teicher, {Beverly A.} and Mark Kunkel and Eric Polley and Lackey, {Karen E.} and Atkinson, {Francis L.} and Overington, {John P.} and Paul Bamborough and Susanne M{\"u}ller and Price, {Daniel J.} and Willson, {Timothy M.} and Drewry, {David H.} and Stefan Knapp and Zuercher, {William J.}",

year = "2016",

month = jan,

day = "1",

doi = "10.1038/nbt.3374",

language = "English",

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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 2016, 'Comprehensive characterization of the Published Kinase Inhibitor Set', Nature Biotechnology, vol. 34, no. 1, pp. 95-103. https://doi.org/10.1038/nbt.3374

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AU - Elkins, Jonathan M.

AU - Fedele, Vita

AU - Szklarz, Marta

AU - Abdul Azeez, Kamal R.

AU - Salah, Eidarus

AU - Mikolajczyk, Jowita

AU - Romanov, Sergei

AU - Sepetov, Nikolai

AU - Huang, Xi Ping

AU - Roth, Bryan L.

AU - Al Haj Zen, Ayman

AU - Fourches, Denis

AU - Muratov, Eugene

AU - Tropsha, Alex

AU - Morris, Joel

AU - Teicher, Beverly A.

AU - Kunkel, Mark

AU - Polley, Eric

AU - Lackey, Karen E.

AU - Atkinson, Francis L.

AU - Overington, John P.

AU - Bamborough, Paul

AU - Müller, Susanne

AU - Price, Daniel J.

AU - Willson, Timothy M.

AU - Drewry, David H.

AU - Knapp, Stefan

AU - Zuercher, William J.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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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DO - 10.1038/nbt.3374

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AN - SCOPUS:84953774679

SN - 1087-0156

VL - 34

SP - 95

EP - 103

JO - Nature Biotechnology

JF - Nature Biotechnology

IS - 1

ER -

Comprehensive characterization of the Published Kinase Inhibitor Set

Abstract

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