Zebrafish as model system for the biological characterization of CK1 inhibitors
Introduction: The CK1 family is involved in a variety of physiological processes by regulating different signaling pathways, including the Wnt/β-catenin, the Hedgehog and the p53 signaling pathways. Mutations or dysregulation of kinases in general and of CK1 in particular are known to promote the de...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1245246/full |
| _version_ | 1797688899478224896 |
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| author | Laura Meier Bernd Martin Gahr Aileen Roth Adrian Gihring Stefan Kirschner Clemens Woitaske-Proske Joana Baier Christian Peifer Steffen Just Uwe Knippschild |
| author_facet | Laura Meier Bernd Martin Gahr Aileen Roth Adrian Gihring Stefan Kirschner Clemens Woitaske-Proske Joana Baier Christian Peifer Steffen Just Uwe Knippschild |
| author_sort | Laura Meier |
| collection | DOAJ |
| description | Introduction: The CK1 family is involved in a variety of physiological processes by regulating different signaling pathways, including the Wnt/β-catenin, the Hedgehog and the p53 signaling pathways. Mutations or dysregulation of kinases in general and of CK1 in particular are known to promote the development of cancer, neurodegenerative diseases and inflammation. There is increasing evidence that CK1 isoform specific small molecule inhibitors, including CK1δ- and CK1ε-specific inhibitors of Wnt production (IWP)-based small molecules with structural similarity to benzimidazole compounds, have promising therapeutic potential.Methods: In this study, we investigated the suitability of the zebrafish model system for the evaluation of such CK1 inhibitors. To this end, the kinetic parameters of human CK1 isoforms were compared with those of zebrafish orthologues. Furthermore, the effects of selective CK1δ inhibition during zebrafish embryonic development were analyzed in vivo.Results: The results revealed that zebrafish CK1δA and CK1δB were inhibited as effectively as human CK1δ by compounds G2-2 with IC50 values of 345 and 270 nM for CK1δA and CK1δB versus 503 nM for human CK1δ and G2-3 exhibiting IC50 values of 514 and 561 nM for zebrafish CK1δA and B, and 562 nM for human CK1δ. Furthermore, the effects of selective CK1δ inhibition on zebrafish embryonic development in vivo revealed phenotypic abnormalities indicative of downregulation of CK1δ. Treatment of zebrafish embryos with selected inhibitors resulted in marked phenotypic changes including blood stasis, heart failure, and tail malformations.Conclusion: The results suggest that the zebrafish is a suitable in vivo assay model system for initial studies of the biological relevance of CK1δ inhibition. |
| first_indexed | 2024-03-12T01:37:12Z |
| format | Article |
| id | doaj.art-77461f23611445b1bde586b3cd5612c0 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-12T01:37:12Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-77461f23611445b1bde586b3cd5612c02023-09-11T04:52:52ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-09-011410.3389/fphar.2023.12452461245246Zebrafish as model system for the biological characterization of CK1 inhibitorsLaura Meier0Bernd Martin Gahr1Aileen Roth2Adrian Gihring3Stefan Kirschner4Clemens Woitaske-Proske5Joana Baier6Christian Peifer7Steffen Just8Uwe Knippschild9Surgery Center, Department of General- and Visceral Surgery, University Hospital Ulm, Ulm, GermanyMolecular Cardiology, Department of Internal Medicine II, University Hospital Ulm, Ulm, GermanySurgery Center, Department of General- and Visceral Surgery, University Hospital Ulm, Ulm, GermanySurgery Center, Department of General- and Visceral Surgery, University Hospital Ulm, Ulm, GermanyInstitute of Pharmacy, Christian-Albrechts-University of Kiel, Kiel, GermanyInstitute of Pharmacy, Christian-Albrechts-University of Kiel, Kiel, GermanyInstitute of Pharmacy, Christian-Albrechts-University of Kiel, Kiel, GermanyInstitute of Pharmacy, Christian-Albrechts-University of Kiel, Kiel, GermanyMolecular Cardiology, Department of Internal Medicine II, University Hospital Ulm, Ulm, GermanySurgery Center, Department of General- and Visceral Surgery, University Hospital Ulm, Ulm, GermanyIntroduction: The CK1 family is involved in a variety of physiological processes by regulating different signaling pathways, including the Wnt/β-catenin, the Hedgehog and the p53 signaling pathways. Mutations or dysregulation of kinases in general and of CK1 in particular are known to promote the development of cancer, neurodegenerative diseases and inflammation. There is increasing evidence that CK1 isoform specific small molecule inhibitors, including CK1δ- and CK1ε-specific inhibitors of Wnt production (IWP)-based small molecules with structural similarity to benzimidazole compounds, have promising therapeutic potential.Methods: In this study, we investigated the suitability of the zebrafish model system for the evaluation of such CK1 inhibitors. To this end, the kinetic parameters of human CK1 isoforms were compared with those of zebrafish orthologues. Furthermore, the effects of selective CK1δ inhibition during zebrafish embryonic development were analyzed in vivo.Results: The results revealed that zebrafish CK1δA and CK1δB were inhibited as effectively as human CK1δ by compounds G2-2 with IC50 values of 345 and 270 nM for CK1δA and CK1δB versus 503 nM for human CK1δ and G2-3 exhibiting IC50 values of 514 and 561 nM for zebrafish CK1δA and B, and 562 nM for human CK1δ. Furthermore, the effects of selective CK1δ inhibition on zebrafish embryonic development in vivo revealed phenotypic abnormalities indicative of downregulation of CK1δ. Treatment of zebrafish embryos with selected inhibitors resulted in marked phenotypic changes including blood stasis, heart failure, and tail malformations.Conclusion: The results suggest that the zebrafish is a suitable in vivo assay model system for initial studies of the biological relevance of CK1δ inhibition.https://www.frontiersin.org/articles/10.3389/fphar.2023.1245246/fullCK1deltaCK1 specific small molecule inhibitorszebrafishCK1 orthologuesheart failureblood stasis |
| spellingShingle | Laura Meier Bernd Martin Gahr Aileen Roth Adrian Gihring Stefan Kirschner Clemens Woitaske-Proske Joana Baier Christian Peifer Steffen Just Uwe Knippschild Zebrafish as model system for the biological characterization of CK1 inhibitors Frontiers in Pharmacology CK1delta CK1 specific small molecule inhibitors zebrafish CK1 orthologues heart failure blood stasis |
| title | Zebrafish as model system for the biological characterization of CK1 inhibitors |
| title_full | Zebrafish as model system for the biological characterization of CK1 inhibitors |
| title_fullStr | Zebrafish as model system for the biological characterization of CK1 inhibitors |
| title_full_unstemmed | Zebrafish as model system for the biological characterization of CK1 inhibitors |
| title_short | Zebrafish as model system for the biological characterization of CK1 inhibitors |
| title_sort | zebrafish as model system for the biological characterization of ck1 inhibitors |
| topic | CK1delta CK1 specific small molecule inhibitors zebrafish CK1 orthologues heart failure blood stasis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1245246/full |
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