TY - JOUR
T1 - The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase
AU - Pierotti, Catia L.
AU - Jacobsen, Annette V.
AU - Grohmann, Christoph
AU - Dempsey, Ruby K.
AU - Etemadi, Nima
AU - Hildebrand, Joanne M.
AU - Fitzgibbon, Cheree
AU - Young, Samuel N.
AU - Davies, Katherine A.
AU - Kersten, Wilhelmus J.A.
AU - Silke, John
AU - Lowes, Kym N.
AU - Sabroux, Hélène Jousset
AU - Huang, David C.S.
AU - van Delft, Mark F.
AU - Murphy, James M.
AU - Lessene, Guillaume
N1 - Funding Information:
C.L.P., A.V.J. and K.A.D. were supported by an Australian Government Research Training Program Stipend Scholarship. We thank the Australian National Health and Medical Research Council (NHMRC) for grant ( J.M.H.: 2011584; J.M.M. and G.L.: 1067289) and fellowship ( J.M.H.: 0541951; J.S.: 1058190 and 1107149; D.C.S.H.: 1156024; J.M.M.: 1172929; G.L.: 1117089 and 2016461) support; Anaxis Pharma Pty Ltd for funding support; and infrastructure support provided by Victorian State Government Operational Infrastructure Support, NHMRC Independent Research Institutes Infrastructure Support Scheme (IRIISS) grant (9000719) and Australian Cancer Research Foundation funding. The Walter and Eliza Hall Institute screening facility is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program.
Funding Information:
C.L.P., A.V.J. and K.A.D. were supported by an Australian Government Research Training Program Stipend Scholarship. We thank the Australian National Health and Medical Research Council (NHMRC) for grant (J.M.H.: 2011584; J.M.M. and G.L.: 1067289) and fellowship (J.M.H.: 0541951; J.S.: 1058190 and 1107149; D.C.S.H.: 1156024; J.M.M.: 1172929; G.L.: 1117089 and 2016461) support; Anaxis Pharma Pty Ltd for funding support; and infrastructure support provided by Victorian State Government Operational Infrastructure Support, NHMRC Independent Research Institutes Infrastructure Support Scheme (IRIISS) grant (9000719) and Australian Cancer Research Foundation funding. The Walter and Eliza Hall Institute screening facility is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We would like to thank Soo San Wan (WEHI) for technical assistance and advice with the phenotypic screen. We thank Kim Newton (Genentech) for kindly providing the p-mRIPK3 antibody; Vishva Dixit and Kim Newton for RIPK3 knockout mice and Michelle Kelliher for the RIPK1 knockout mouse strain, from which MDF cells were generated.
Publisher Copyright:
© 2023 The Author(s). 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).
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85159734992
U2 - 10.1042/BCJ20230035
DO - 10.1042/BCJ20230035
M3 - Article
C2 - 37115711
AN - SCOPUS:85159734992
SN - 0264-6021
VL - 480
SP - 665
EP - 684
JO - Biochemical Journal
JF - Biochemical Journal
IS - 9
ER -
SDG 3 Good Health and Well-being