Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases
The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 15...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2024.2394895 |
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| author | Ashley P. Dudey Jake M. Rigby Gregory R. Hughes G. Richard Stephenson Thomas E. Storr Andrew Chantry Andrew M. Hemmings |
| author_facet | Ashley P. Dudey Jake M. Rigby Gregory R. Hughes G. Richard Stephenson Thomas E. Storr Andrew Chantry Andrew M. Hemmings |
| author_sort | Ashley P. Dudey |
| collection | DOAJ |
| description | The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development. |
| format | Article |
| id | doaj-art-9ea481d25ddf466492f4e323196ebb63 |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-9ea481d25ddf466492f4e323196ebb632025-08-20T02:35:33ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2024.2394895Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligasesAshley P. Dudey0Jake M. Rigby1Gregory R. Hughes2G. Richard Stephenson3Thomas E. Storr4Andrew Chantry5Andrew M. Hemmings6School of Biological Sciences, University of East Anglia, Norwich, UKSchool of Chemistry, Pharmacy & Pharmacology, University of East Anglia, Norwich, UKSchool of Biological Sciences, University of East Anglia, Norwich, UKSchool of Chemistry, Pharmacy & Pharmacology, University of East Anglia, Norwich, UKSchool of Chemistry, Pharmacy & Pharmacology, University of East Anglia, Norwich, UKSchool of Biological Sciences, University of East Anglia, Norwich, UKSchool of Biological Sciences, University of East Anglia, Norwich, UKThe HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC50 of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC50 of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.https://www.tandfonline.com/doi/10.1080/14756366.2024.2394895ubiquitin ligase inhibitorsdrug discoverySARWWP1WWP2 |
| spellingShingle | Ashley P. Dudey Jake M. Rigby Gregory R. Hughes G. Richard Stephenson Thomas E. Storr Andrew Chantry Andrew M. Hemmings Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases Journal of Enzyme Inhibition and Medicinal Chemistry ubiquitin ligase inhibitors drug discovery SAR WWP1 WWP2 |
| title | Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases |
| title_full | Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases |
| title_fullStr | Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases |
| title_full_unstemmed | Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases |
| title_short | Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases |
| title_sort | expanding the inhibitor space of the wwp1 and wwp2 hect e3 ligases |
| topic | ubiquitin ligase inhibitors drug discovery SAR WWP1 WWP2 |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2024.2394895 |
| work_keys_str_mv | AT ashleypdudey expandingtheinhibitorspaceofthewwp1andwwp2hecte3ligases AT jakemrigby expandingtheinhibitorspaceofthewwp1andwwp2hecte3ligases AT gregoryrhughes expandingtheinhibitorspaceofthewwp1andwwp2hecte3ligases AT grichardstephenson expandingtheinhibitorspaceofthewwp1andwwp2hecte3ligases AT thomasestorr expandingtheinhibitorspaceofthewwp1andwwp2hecte3ligases AT andrewchantry expandingtheinhibitorspaceofthewwp1andwwp2hecte3ligases AT andrewmhemmings expandingtheinhibitorspaceofthewwp1andwwp2hecte3ligases |