The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase

Pierotti, CL; Jacobsen, AV; Grohmann, C; Dempsey, RK; Etemadi, N; Hildebrand, JM; Fitzgibbon, C; Young, SN; Davies, KA; Kersten, WJA; Silke, J; Lowes, KN; Jousset Sabroux, H; Huang, DCS; van Delft, MF; Murphy, JM; Lessene, G

Author(s): Pierotti, CL; Jacobsen, AV; Grohmann, C; Dempsey, RK; Etemadi, N; Hildebrand, JM; Fitzgibbon, C; Young, SN; Davies, KA; Kersten, WJA; Silke, J; Lowes, KN; Jousset Sabroux, H; Huang, DCS; van Delft, MF; Murphy, JM; Lessene, G;
Details: Publication Year 2023,Volume 480,Issue #9,Page 665-684
Journal Title: Biochemical Journal
Abstract: 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.
Publisher: Portland Press
Keywords: Humans; Tyrosine Protein Kinase Inhibitors; Protein Kinases/genetics/metabolism; Necroptosis; Vascular Endothelial Growth Factor A/metabolism; Apoptosis; Receptors, Vascular Endothelial Growth Factor/metabolism; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism; kinase inhibitor; protein-serine-threonine kinases; signalling
Research Division(s): Chemical Biology; Advanced Technology And Biology; Blood Cells And Blood Cancer; Inflammation
PubMed ID: 37115711
Publisher's Version: https://doi.org/10.1042/bcj20230035
Open Access at Publisher's Site: https://doi.org/10.1042/BCJ20230035
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-06-07 03:08:31

Last Modified: 2023-06-07 03:25:08