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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

DOI

10.1002/cmdc.202000150

Type

Journal article

Journal

ChemMedChem

Publication Date

03/07/2020

Volume

15

Pages

1200 - 1215

Keywords

WaterMap, anilinoquinazolines, anilinoquinolines, cyclin G-associated kinase (GAK), water networks