Abstract
4-Anilinoquinolines were identified as potent and narrow-spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator of viral and bacterial entry into host cells. Optimization of the 4-anilino group and the 6,7-quinoline substituents produced GAK inhibitors with nanomolar activity, over 50 000-fold selectivity relative to other members of the numb-associated kinase (NAK) subfamily, and a compound (6,7-dimethoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine; 49) with a narrow-spectrum kinome profile. These compounds may be useful tools to explore the therapeutic potential of GAK in prevention of a broad range of infectious and systemic diseases.
Keywords:
anilinoquinolines; antibacterial agents; chemical probes; cyclin G associated kinase (GAK).
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / chemistry*
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Aniline Compounds / metabolism
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Aniline Compounds / pharmacology
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Binding Sites
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Catalytic Domain
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Drug Design
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Endocytosis / drug effects
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / metabolism*
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Kinetics
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Molecular Docking Simulation
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Protein Binding
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism*
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Quinazolines / chemistry*
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Quinazolines / metabolism
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Quinazolines / pharmacology
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Structure-Activity Relationship
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Viruses / pathogenicity
Substances
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Aniline Compounds
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Intracellular Signaling Peptides and Proteins
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Protein Kinase Inhibitors
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Quinazolines
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anilinoquinazoline
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GAK protein, human
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Protein Serine-Threonine Kinases