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Targeting the Water Network in Cyclin G-Associated Kinase (GAK) with 4-Anilino-quin(az)oline Inhibitors |
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| Authors: | Dr Christopher R M Asquith Dr Graham J Tizzard James M Bennett Carrow I Wells Dr Jonathan M Elkins Prof Timothy M Willson Prof Antti Poso Dr Tuomo Laitinen |
| Affiliation: | 1. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA;2. UK National Crystallography Service, School of Chemistry, University of Southampton, Southampton, SO17 1BJ UK;3. Structural Genomics Consortium and Target Discovery Institute Nuffield Department of Clinical Medicine, University of Oxford Old Road Campus Research Building, Oxford, OX3 7DQ UK).;4. Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA;5. Structural Genomics Consortium and Target Discovery Institute Nuffield Department of Clinical Medicine, University of Oxford Old Road Campus Research Building, Oxford, OX3 7DQ UK).
Structural Genomics Consortium, Universidade Estadual de Campinas – UNICAMP Campinas, São Paulo, 13083-886 Brazil;6. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland University Hospital Tübingen Department of Internal Medicine VIII, University of Tübingen, 72076 Tübingen, Germany;7. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland |
| 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: | anilinoquinazolines anilinoquinolines cyclin G-associated kinase (GAK) water networks WaterMap |