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

View ORCID ProfileChristopher R. M. Asquith, View ORCID ProfileGraham J. Tizzard, James M. Bennett, View ORCID ProfileCarrow I. Wells, Jonathan M. Elkins, View ORCID ProfileTimothy M. Willson, View ORCID ProfileAntti Poso, View ORCID ProfileTuomo Laitinen
doi: https://doi.org/10.1101/2020.03.06.976563
Christopher R. M. Asquith
aDepartment of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, NC 27599, (USA), E-mail:
bStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, (USA)
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  • For correspondence: chris.asquith@unc.edu chris.asquith@unc.edu
Graham J. Tizzard
cSchool of Chemistry, University of Southampton, Southampton, SO17 1BJ, (UK)
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James M. Bennett
dStructural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, (UK)
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Carrow I. Wells
bStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, (USA)
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Jonathan M. Elkins
dStructural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, (UK)
eStructural Genomics Consortium, Universidade Estadual de Campinas - UNICAMP, Campinas, São Paulo, 13083-886, (Brazil)
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Timothy M. Willson
bStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, (USA)
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Antti Poso
fSchool of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, (Finland)
gUniversity Hospital Tübingen, Department of Internal Medicine VIII, University of Tübingen, 72076 Tübingen (Germany)
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Tuomo Laitinen
fSchool of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, (Finland)
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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 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted March 07, 2020.
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Targeting the water network in cyclin G associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors
Christopher R. M. Asquith, Graham J. Tizzard, James M. Bennett, Carrow I. Wells, Jonathan M. Elkins, Timothy M. Willson, Antti Poso, Tuomo Laitinen
bioRxiv 2020.03.06.976563; doi: https://doi.org/10.1101/2020.03.06.976563
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Targeting the water network in cyclin G associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors
Christopher R. M. Asquith, Graham J. Tizzard, James M. Bennett, Carrow I. Wells, Jonathan M. Elkins, Timothy M. Willson, Antti Poso, Tuomo Laitinen
bioRxiv 2020.03.06.976563; doi: https://doi.org/10.1101/2020.03.06.976563

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