Premium
Targeting the Water Network in Cyclin G‐Associated Kinase (GAK) with 4‐Anilino‐quin(az)oline Inhibitors
Author(s) -
Asquith Christopher R. M.,
Tizzard Graham J.,
Bennett James M.,
Wells Carrow I.,
Elkins Jonathan M.,
Willson Timothy M.,
Poso Antti,
Laitinen Tuomo
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000150
Subject(s) - kinase , drug discovery , chemistry , cyclin dependent kinase , cyclin , potency , biochemistry , computational biology , biology , in vitro , gene , cell cycle
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.