PT  - JOURNAL ARTICLE
AU  - Asquith, Christopher R. M.
AU  - Tizzard, Graham J.
AU  - Bennett, James M.
AU  - Wells, Carrow I.
AU  - Elkins, Jonathan M.
AU  - Willson, Timothy M.
AU  - Poso, Antti
AU  - Laitinen, Tuomo
TI  - Targeting the water network in cyclin G associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors
AID  - 10.1101/2020.03.06.976563
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.06.976563
4099  - http://biorxiv.org/content/early/2020/03/07/2020.03.06.976563.short
4100  - http://biorxiv.org/content/early/2020/03/07/2020.03.06.976563.full
AB  - 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 on target. Here we describe the design and testing of a targeted library of 4-anilinoquinolines for use as inhibitors of cyclin G associated kinase (GAK). The 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.