Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors

Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors

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 th...

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Библиографические подробности
Главные авторы: Asquith, CRM, Tizzard, GJ, Bennett, JM, Wells, CI, Elkins, JM, Willson, TM, Poso, A, Laitinen, T
Формат: Journal article
Язык:English
Опубликовано: Wiley 2020
Описание
Итог: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.

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