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...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Wiley
2020
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| _version_ | 1826296658820857856 |
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| author | Asquith, CRM Tizzard, GJ Bennett, JM Wells, CI Elkins, JM Willson, TM Poso, A Laitinen, T |
| author_facet | Asquith, CRM Tizzard, GJ Bennett, JM Wells, CI Elkins, JM Willson, TM Poso, A Laitinen, T |
| author_sort | Asquith, CRM |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T04:19:44Z |
| format | Journal article |
| id | oxford-uuid:ca9c935c-18c1-4345-9d95-b4879e8d726a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:19:44Z |
| publishDate | 2020 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:ca9c935c-18c1-4345-9d95-b4879e8d726a2022-03-27T07:08:40ZTargeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitorsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ca9c935c-18c1-4345-9d95-b4879e8d726aEnglishSymplectic ElementsWiley2020Asquith, CRMTizzard, GJBennett, JMWells, CIElkins, JMWillson, TMPoso, ALaitinen, TWater 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. |
| spellingShingle | Asquith, CRM Tizzard, GJ Bennett, JM Wells, CI Elkins, JM Willson, TM Poso, A Laitinen, T Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors |
| title | Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors |
| title_full | Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors |
| title_fullStr | Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors |
| title_full_unstemmed | Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors |
| title_short | Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitors |
| title_sort | targeting the water network in cyclin g associated kinase gak with 4 anilino quin az oline inhibitors |
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