Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury

  • Necroptosis contributes to the pathophysiology of several inflammatory, infectious and degenerative disorders. TNF-induced necroptosis involves activation of the receptor-interacting protein kinases 1 and 3 (RIPK1/3) in a necrosome complex, eventually leading to the phosphorylation and relocation of mixed lineage kinase domain like protein (MLKL). Using a high-content screening of small compounds and FDA-approved drug libraries, we identified the anti-cancer drug Sorafenib tosylate as a potent inhibitor of TNF-dependent necroptosis. Interestingly, Sorafenib has a dual activity spectrum depending on its concentration. In murine and human cell lines it induces cell death, while at lower concentrations it inhibits necroptosis, without affecting NF-κB activation. Pull down experiments with biotinylated Sorafenib show that it binds independently RIPK1, RIPK3 and MLKL. Moreover, it inhibits RIPK1 and RIPK3 kinase activity. In vivo Sorafenib protects against TNF-induced systemic inflammatory response syndrome (SIRS) and renal ischemia–reperfusion injury (IRI). Altogether, we show that Sorafenib can, next to the reported Braf/Mek/Erk and VEGFR pathways, also target the necroptotic pathway and that it can protect in an acute inflammatory RIPK1/3-mediated pathology.

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Author:Sofie Martens, Manhyung Jeong, Wulf Tonnus, Friederike Feldmann, Sam Hofmans, Vera Goossens, Nozomi Takahashi, Jan Hinrich Bräsen, Eun-Woo Lee, Pieter van der Veken, Jurgen Joossens, Koen Augustyns, Simone FuldaORCiDGND, Andreas Linkermann, Jaewhan Song, Peter Vandenabeele
Pubmed Id:
Parent Title (English):Cell death & disease
Publisher:Nature Publishing Group
Place of publication:London [u. a.]
Contributor(s):G. Raschellà
Document Type:Article
Year of Completion:2017
Date of first Publication:2017/06/29
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/04/17
Issue:6, e2904
Page Number:12
First Page:1
Last Page:12
Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0