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

Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitor
Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitor
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.
Water Map, Water networks, anilinoquinazolines, anilinoquinolines, cyclin G-associated kinase (GAK)
1860-7179
1200-1215
Asquith, Christopher RM
c00d3c3f-08c5-4c9a-bac8-0fc485db1be4
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Bennett, James M.
296a6be7-1eb3-4bc1-b89c-83668a2996e5
Wells, Carrow I.
b1b55315-9748-46cb-919f-663298061454
Elkins, Jonathan M.
103a8855-1ca0-4abb-9ce2-a7c4f350fe39
Wilson, Timothy M.
2935e59e-8856-488b-a1b3-266361256661
Poso, Antti
84d2fb32-9d24-4ad9-a9ca-a66e3cab8a3d
Laitinen, Tuomo
b37037c5-4eac-4533-8246-5a49213bae9b
Asquith, Christopher RM
c00d3c3f-08c5-4c9a-bac8-0fc485db1be4
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Bennett, James M.
296a6be7-1eb3-4bc1-b89c-83668a2996e5
Wells, Carrow I.
b1b55315-9748-46cb-919f-663298061454
Elkins, Jonathan M.
103a8855-1ca0-4abb-9ce2-a7c4f350fe39
Wilson, Timothy M.
2935e59e-8856-488b-a1b3-266361256661
Poso, Antti
84d2fb32-9d24-4ad9-a9ca-a66e3cab8a3d
Laitinen, Tuomo
b37037c5-4eac-4533-8246-5a49213bae9b

Asquith, Christopher RM, Tizzard, Graham J., Bennett, James M., Wells, Carrow I., Elkins, Jonathan M., Wilson, Timothy M., Poso, Antti and Laitinen, Tuomo (2020) Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitor. ChemMedChem, 15 (13), 1200-1215. (doi:10.1002/cmdc.202000150).

Record type: Article

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.

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202000150 - Accepted Manuscript
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Accepted/In Press date: 1 May 2020
e-pub ahead of print date: 1 May 2020
Published date: 3 July 2020
Additional Information: Funding Information: The SGC is a registered charity (no. 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medi‐cines Initiative (EU/EFPIA) [ULTRA‐DD grant no. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation‐FAPESP, Takeda, and Wellcome [106169/ZZ14/Z]. We also thank CSC – IT Center for Science Ltd. Finland for the use of their facilities, software licenses, computational resources and the Biocenter Finland/DDCB for financial support. The authors thank Prof. Lee Graves (University of North Carolina at Chapel Hill), Dr. Louisa Temme (Universität Münster) and Dr. Carla Alamillo‐Ferrer (University of Manchester) for useful discussions. We are grateful to Dr. Brandie Ehrmann for LC‐MS/HRMS support provided by the Mass Spectrometry Core Laboratory at the University of North Carolina at Chapel Hill. We also thank the EPSRC UK National Crystallography Service for funding and collection of the crystallographic data for 13 , 14 , 25 , 27 and 29 . Publisher Copyright: © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Keywords: Water Map, Water networks, anilinoquinazolines, anilinoquinolines, cyclin G-associated kinase (GAK)

Identifiers

Local EPrints ID: 441843
URI: http://eprints.soton.ac.uk/id/eprint/441843
ISSN: 1860-7179
PURE UUID: e71e7e95-6f0c-4a18-89f7-fc4dc37ae780
ORCID for Graham J. Tizzard: ORCID iD orcid.org/0000-0002-1577-5779

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Date deposited: 30 Jun 2020 16:30
Last modified: 06 Oct 2022 04:01

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Contributors

Author: Christopher RM Asquith
Author: James M. Bennett
Author: Carrow I. Wells
Author: Jonathan M. Elkins
Author: Timothy M. Wilson
Author: Antti Poso
Author: Tuomo Laitinen

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