Abstract
Water networks within kinase inhibitor design and more widely within drug discovery are generally poorly understood. The successful targeting of these networks prospectively has great promise for all facets of inhibitor design, including potency and selectivity for the target. Herein, we describe the design and testing of a targeted library of 4-anilinoquin(az)olines for use as inhibitors of cyclin G-associated kinase (GAK). GAK cellular target engagement assays, ATP binding-site modelling and extensive water mapping provide a clear route to access potent inhibitors for GAK and beyond.
Keywords:
WaterMap; anilinoquinazolines; anilinoquinolines; cyclin G-associated kinase (GAK); water networks.
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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HEK293 Cells
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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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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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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 / chemical synthesis
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Quinazolines / chemistry
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Quinazolines / pharmacology*
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Structure-Activity Relationship
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Water / chemistry*
Substances
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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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Water
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GAK protein, human
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Protein Serine-Threonine Kinases