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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... Full description

Journal Title: Nature biotechnology 2016-01, Vol.34 (1), p.95-103
Main Author: Elkins, Jonathan M
Other Authors: Fedele, Vita , Szklarz, Marta , Abdul Azeez, Kamal R , Salah, Eidarus , Mikolajczyk, Jowita , Romanov, Sergei , Sepetov, Nikolai , Huang, Xi-Ping , Roth, Bryan L , Al Haj Zen, Ayman , Fourches, Denis , Muratov, Eugene , Tropsha, Alex , Morris, Joel , Teicher, Beverly A , Kunkel, Mark , Polley, Eric , Lackey, Karen E , Atkinson, Francis L , Overington, John P , Bamborough, Paul , Müller, Susanne , Price, Daniel J , Willson, Timothy M , Drewry, David H , Knapp, Stefan , Zuercher, William J
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: United States: Nature Publishing Group
ID: ISSN: 1087-0156
Link: https://www.ncbi.nlm.nih.gov/pubmed/26501955
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recordid: cdi_proquest_miscellaneous_1765976957
title: Comprehensive characterization of the Published Kinase Inhibitor Set
format: Article
creator:
  • Elkins, Jonathan M
  • Fedele, Vita
  • Szklarz, Marta
  • Abdul Azeez, Kamal R
  • Salah, Eidarus
  • Mikolajczyk, Jowita
  • Romanov, Sergei
  • Sepetov, Nikolai
  • Huang, Xi-Ping
  • Roth, Bryan L
  • Al Haj Zen, Ayman
  • Fourches, Denis
  • Muratov, Eugene
  • Tropsha, Alex
  • Morris, Joel
  • Teicher, Beverly A
  • Kunkel, Mark
  • Polley, Eric
  • Lackey, Karen E
  • Atkinson, Francis L
  • Overington, John P
  • Bamborough, Paul
  • Müller, Susanne
  • Price, Daniel J
  • Willson, Timothy M
  • Drewry, David H
  • Knapp, Stefan
  • Zuercher, William J
subjects:
  • Glycosylation
  • Inhibitor drugs
  • Kinases
  • Molecular biology
  • Molecular targeted therapy
  • Pharmaceutical sciences
  • Phosphotransferases - antagonists & inhibitors
  • Physiological aspects
  • Protein Kinase Inhibitors - pharmacology
  • Protein kinases
  • Protein research
ispartof: Nature biotechnology, 2016-01, Vol.34 (1), p.95-103
description: 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.
language: eng
source:
identifier: ISSN: 1087-0156
fulltext: no_fulltext
issn:
  • 1087-0156
  • 1546-1696
url: Link


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titleComprehensive characterization of the Published Kinase Inhibitor Set
creatorElkins, Jonathan M ; Fedele, Vita ; Szklarz, Marta ; Abdul Azeez, Kamal R ; Salah, Eidarus ; Mikolajczyk, Jowita ; Romanov, Sergei ; Sepetov, Nikolai ; Huang, Xi-Ping ; Roth, Bryan L ; Al Haj Zen, Ayman ; Fourches, Denis ; Muratov, Eugene ; Tropsha, Alex ; Morris, Joel ; Teicher, Beverly A ; Kunkel, Mark ; Polley, Eric ; Lackey, Karen E ; Atkinson, Francis L ; Overington, John P ; Bamborough, Paul ; Müller, Susanne ; Price, Daniel J ; Willson, Timothy M ; Drewry, David H ; Knapp, Stefan ; Zuercher, William J
creatorcontribElkins, Jonathan M ; Fedele, Vita ; Szklarz, Marta ; Abdul Azeez, Kamal R ; Salah, Eidarus ; Mikolajczyk, Jowita ; Romanov, Sergei ; Sepetov, Nikolai ; Huang, Xi-Ping ; Roth, Bryan L ; Al Haj Zen, Ayman ; Fourches, Denis ; Muratov, Eugene ; Tropsha, Alex ; Morris, Joel ; Teicher, Beverly A ; Kunkel, Mark ; Polley, Eric ; Lackey, Karen E ; Atkinson, Francis L ; Overington, John P ; Bamborough, Paul ; Müller, Susanne ; Price, Daniel J ; Willson, Timothy M ; Drewry, David H ; Knapp, Stefan ; Zuercher, William J
descriptionDespite 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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subjectGlycosylation ; Inhibitor drugs ; Kinases ; Molecular biology ; Molecular targeted therapy ; Pharmaceutical sciences ; Phosphotransferases - antagonists & inhibitors ; Physiological aspects ; Protein Kinase Inhibitors - pharmacology ; Protein kinases ; Protein research
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descriptionDespite 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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authorElkins, Jonathan M ; Fedele, Vita ; Szklarz, Marta ; Abdul Azeez, Kamal R ; Salah, Eidarus ; Mikolajczyk, Jowita ; Romanov, Sergei ; Sepetov, Nikolai ; Huang, Xi-Ping ; Roth, Bryan L ; Al Haj Zen, Ayman ; Fourches, Denis ; Muratov, Eugene ; Tropsha, Alex ; Morris, Joel ; Teicher, Beverly A ; Kunkel, Mark ; Polley, Eric ; Lackey, Karen E ; Atkinson, Francis L ; Overington, John P ; Bamborough, Paul ; Müller, Susanne ; Price, Daniel J ; Willson, Timothy M ; Drewry, David H ; Knapp, Stefan ; Zuercher, William J
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5Pharmaceutical sciences
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7Physiological aspects
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abstractDespite 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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