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The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase
Necroptosis is a mode of programmed, lytic cell death that is executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following activation by the upstream kinases, receptor-interacting serine/threonine protein kinase (RIPK)-1 and RIPK3. Dysregulated necroptosis has been implicated in th...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10212518/ https://www.ncbi.nlm.nih.gov/pubmed/37115711 http://dx.doi.org/10.1042/BCJ20230035 |
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author | Pierotti, Catia L. Jacobsen, Annette V. Grohmann, Christoph Dempsey, Ruby K. Etemadi, Nima Hildebrand, Joanne M. Fitzgibbon, Cheree Young, Samuel N. Davies, Katherine A. Kersten, Wilhelmus J. A. Silke, John Lowes, Kym N. Jousset Sabroux, Hélène Huang, David C. S. van Delft, Mark F. Murphy, James M. Lessene, Guillaume |
author_facet | Pierotti, Catia L. Jacobsen, Annette V. Grohmann, Christoph Dempsey, Ruby K. Etemadi, Nima Hildebrand, Joanne M. Fitzgibbon, Cheree Young, Samuel N. Davies, Katherine A. Kersten, Wilhelmus J. A. Silke, John Lowes, Kym N. Jousset Sabroux, Hélène Huang, David C. S. van Delft, Mark F. Murphy, James M. Lessene, Guillaume |
author_sort | Pierotti, Catia L. |
collection | PubMed |
description | Necroptosis is a mode of programmed, lytic cell death that is executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following activation by the upstream kinases, receptor-interacting serine/threonine protein kinase (RIPK)-1 and RIPK3. Dysregulated necroptosis has been implicated in the pathophysiology of many human diseases, including inflammatory and degenerative conditions, infectious diseases and cancers, provoking interest in pharmacological targeting of the pathway. To identify small molecules impacting on the necroptotic machinery, we performed a phenotypic screen using a mouse cell line expressing an MLKL mutant that kills cells in the absence of upstream death or pathogen detector receptor activation. This screen identified the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinase inhibitor, ABT-869 (Linifanib), as a small molecule inhibitor of necroptosis. We applied a suite of cellular, biochemical and biophysical analyses to pinpoint the apical necroptotic kinase, RIPK1, as the target of ABT-869 inhibition. Our study adds to the repertoire of established protein kinase inhibitors that additionally target RIPK1 and raises the prospect that serendipitous targeting of necroptosis signalling may contribute to their clinical efficacy in some settings. |
format | Online Article Text |
id | pubmed-10212518 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-102125182023-05-26 The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase Pierotti, Catia L. Jacobsen, Annette V. Grohmann, Christoph Dempsey, Ruby K. Etemadi, Nima Hildebrand, Joanne M. Fitzgibbon, Cheree Young, Samuel N. Davies, Katherine A. Kersten, Wilhelmus J. A. Silke, John Lowes, Kym N. Jousset Sabroux, Hélène Huang, David C. S. van Delft, Mark F. Murphy, James M. Lessene, Guillaume Biochem J Cell Death & Injury Necroptosis is a mode of programmed, lytic cell death that is executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following activation by the upstream kinases, receptor-interacting serine/threonine protein kinase (RIPK)-1 and RIPK3. Dysregulated necroptosis has been implicated in the pathophysiology of many human diseases, including inflammatory and degenerative conditions, infectious diseases and cancers, provoking interest in pharmacological targeting of the pathway. To identify small molecules impacting on the necroptotic machinery, we performed a phenotypic screen using a mouse cell line expressing an MLKL mutant that kills cells in the absence of upstream death or pathogen detector receptor activation. This screen identified the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinase inhibitor, ABT-869 (Linifanib), as a small molecule inhibitor of necroptosis. We applied a suite of cellular, biochemical and biophysical analyses to pinpoint the apical necroptotic kinase, RIPK1, as the target of ABT-869 inhibition. Our study adds to the repertoire of established protein kinase inhibitors that additionally target RIPK1 and raises the prospect that serendipitous targeting of necroptosis signalling may contribute to their clinical efficacy in some settings. Portland Press Ltd. 2023-05-12 /pmc/articles/PMC10212518/ /pubmed/37115711 http://dx.doi.org/10.1042/BCJ20230035 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . Open access for this article was enabled by the participation of the University of Melbourne in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with CAUL. |
spellingShingle | Cell Death & Injury Pierotti, Catia L. Jacobsen, Annette V. Grohmann, Christoph Dempsey, Ruby K. Etemadi, Nima Hildebrand, Joanne M. Fitzgibbon, Cheree Young, Samuel N. Davies, Katherine A. Kersten, Wilhelmus J. A. Silke, John Lowes, Kym N. Jousset Sabroux, Hélène Huang, David C. S. van Delft, Mark F. Murphy, James M. Lessene, Guillaume The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase |
title | The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase |
title_full | The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase |
title_fullStr | The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase |
title_full_unstemmed | The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase |
title_short | The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase |
title_sort | vegfr/pdgfr tyrosine kinase inhibitor, abt-869, blocks necroptosis by targeting ripk1 kinase |
topic | Cell Death & Injury |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10212518/ https://www.ncbi.nlm.nih.gov/pubmed/37115711 http://dx.doi.org/10.1042/BCJ20230035 |
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