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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.

Original publication




Journal article



Publication Date





1200 - 1215


Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.


Humans, Water, Quinazolines, Protein-Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins, Protein Kinase Inhibitors, Crystallography, X-Ray, Molecular Structure, Structure-Activity Relationship, Dose-Response Relationship, Drug, Models, Molecular, HEK293 Cells