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

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.

Repurposing of Ibrutinib and Quizartinib as potent inhibitors of necroptosis

“…2c and Supplementary Data 3 ). Interestingly, linifanib was recently reported to be RIPK1 kinase inhibitor 36 , 37 . Similarly, we classified the remaining compounds as GSK’872-like inhibitors, NEC-1 plus GSK’872-like inhibitors, or other types of inhibitors (Fig.…”

Cellular heterogeneity in TNF/TNFR1 signalling: live cell imaging of cell fate decisions in single cells

“…Live-cell imaging has been the technique of choice to study these processes. Whilst this approach has been employed extensively to investigate TNF-induced inflammation [ 18 , 23 , 31 – 33 ], and to some extent TNF-induced cell death [ 34 – 36 ], the role of TNF/TNFR1 signalling pathway crosstalk in guiding cell-fate decisions in single cells has been understudied. It is vital to understand the mechanisms driving cell-to-cell variability in response to TNF and modulators of the TNF/TNFR1 signalling pathway, as drugs designed to promote TNF-induced cell death suffer from fractional killing [ 37 – 40 ], and poor responses in various cell lines [ 39 , 41 ].…”