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

Catia L Pierotti; Annette V Jacobsen; Christoph Grohmann; Ruby K Dempsey; Nima Etemadi; Joanne M Hildebrand; Cheree Fitzgibbon; Samuel N Young; Katherine A Davies; Wilhelmus J A Kersten; John Silke; Kym N Lowes; Hélène Jousset Sabroux; David C S Huang; Mark F van Delft; James M Murphy; Guillaume Lessene

doi:10.1042/BCJ20230035

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

Biochem J. 2023 May 15;480(9):665-684. doi: 10.1042/BCJ20230035.

Authors

Catia L Pierotti^{1

2}, Annette V Jacobsen^{1

2}, Christoph Grohmann^{1

2}, Ruby K Dempsey^{1

2}, Nima Etemadi^{1

2}, Joanne M Hildebrand^{1

2}, Cheree Fitzgibbon^{1

2}, Samuel N Young¹, Katherine A Davies^{1

2}, Wilhelmus J A Kersten¹, John Silke^{1

2}, Kym N Lowes^{1

2}, Hélène Jousset Sabroux^{1

2}, David C S Huang^{1

2}, Mark F van Delft^{1

2}, James M Murphy^{1

2

3}, Guillaume Lessene^{1

2

4}

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
² Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
³ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
⁴ Department of Biochemistry and Therapeutics, University of Melbourne, Parkville, VIC 3052, Australia.

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.

Keywords: kinase inhibitor; necroptosis; protein-serine-threonine kinases; signalling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Humans
Necroptosis
Protein Kinases* / genetics
Protein Kinases* / metabolism
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
Receptors, Vascular Endothelial Growth Factor / metabolism
Tyrosine Kinase Inhibitors*
Vascular Endothelial Growth Factor A / metabolism

Substances

Tyrosine Kinase Inhibitors
Protein Kinases
Vascular Endothelial Growth Factor A
Receptors, Vascular Endothelial Growth Factor
Receptor-Interacting Protein Serine-Threonine Kinases
RIPK1 protein, human