Small molecule inhibitor binds RIPK1, RIPK3

Stable Identifier
Reaction [binding]
Homo sapiens
Sorafenib, pazopanib or ponatinib binds RIPK1, RIPK3
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Several FDA-approved anticancer drugs, including sorafenib, pazopanib and ponatinib showed anti-necroptotic activity (Fauster A et al. 2015; Martens S et al. 2017; Fulda S 2018). Sorafenib was identified as an inhibitor of necroptosis using a high-content screening of FDA-approved drug libraries and small compounds (Martens S et al. 2017). Sorafenib has been demonstrated to block kinase activity of both receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 by targeting their inactive states (Martens S et al. 2017). In pull-down experiments, biotinylated sorafenib has been found to directly interact with RIPK1, RIPK3 and MLKL (Martens S et al. 2017). Consequently, sorafenib rescued murine as well as human cell lines from TNFα-stimulated necroptosis (Martens S et al. 2017). Also, sorafenib can protect apoptosis-resistant acute myeloid leukemia (AML) cells from second mitochondria-derived activator of caspases (SMAC) mimetic-induced necroptosis, including primary, patient-derived AML blasts (Feldmann F et al. 2017). Importantly, sorafenib has been shown to provide protection in two in vivo models of necroptosis, that is in renal ischemia-reperfusion injury and in TNF-induced systemic inflammatory response syndrome (Martens S et al. 2017). Sorafenib was unable to inhibit necroptosis in mouse dermal fibroblasts (MDFs) (Hildebrand JM et al. 2014). In addition to sorafenib, a cellular screen with FDA-approved drugs identified pazopanib and ponatinib as necroptosis inhibitors that suppressed necroptosis in human cells at submicromolar EC50 concentrations (Fauster A et al. 2015). Both drugs inhibited necroptotic signaling triggered by various cell death receptors, whereas they did not interfere with apoptosis. Ponatinib and pazopanib abrogated phosphorylation of MLKL upon TNF-α-induced necroptosis in human adenocarcinoma HT-29 cells, suggesting that both agents target a component upstream of MLKL (Fauster A et al. 2015). RIPK1 has been identified as the main functional target of pazopanib, while ponatinib directly targeted both RIPK1 and RIPK3 (Fauster A et al. 2015; Najjar M et al. 2015).
Literature References
PubMed ID Title Journal Year
25996294 A cellular screen identifies ponatinib and pazopanib as inhibitors of necroptosis

Krautwald, S, Stukalov, A, Bruckner, M, Superti-Furga, G, Fauster, A, Huber, KV, Bennett, KL, Kubicek, S, Rebsamen, M, Lardeau, CH, Gridling, M, Colinge, J, Parapatics, K, Linkermann, A, Bigenzahn, JW, Scorzoni, S

Cell Death Dis 2015
28661484 Sorafenib tosylate inhibits directly necrosome complex formation and protects in mouse models of inflammation and tissue injury

Bräsen, JH, Feldmann, F, Tonnus, W, Takahashi, N, Hofmans, S, Augustyns, K, Van der Veken, P, Song, J, Vandenabeele, P, Lee, EW, Linkermann, A, Goossens, V, Joossens, J, Martens, S, Fulda, S, Jeong, M

Cell Death Dis 2017
Event Information
Orthologous Events
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