A cellular screen identifies ponatinib and pazopanib as inhibitors of necroptosis
| Autor: | Stefan Kubicek, Astrid Fauster, Alexey Stukalov, Johannes W. Bigenzahn, Manuela Gridling, Manuele Rebsamen, Stefan Krautwald, Katja Parapatics, Andreas Linkermann, Manuela Bruckner, C-H Lardeau, Keiryn L. Bennett, Kilian Huber, Jacques Colinge, Stefania Scorzoni, Giulio Superti-Furga |
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| Přispěvatelé: | Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria] (CeMM ), Austrian Academy of Sciences (OeAW), Max-Planck-Institut für Physik (Werner-Heisenberg-Institut) (MPI-P), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Christian-Albrechts University of Kiel |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Fas-Associated Death Domain Protein Apoptosis Pharmacology Jurkat Cells Mice chemistry.chemical_compound L Cells 0302 clinical medicine FADD Phosphorylation Sulfonamides 0303 health sciences Ponatinib Imidazoles 3T3 Cells MAP Kinase Kinase Kinases 3. Good health Pyridazines Receptor-Interacting Protein Serine-Threonine Kinases 030220 oncology & carcinogenesis Necroptosis Original Article HT29 Cells Protein Binding medicine.drug Programmed cell death Indazoles Immunology [SDV.CAN]Life Sciences [q-bio]/Cancer Biology Pazopanib Necrosis 03 medical and health sciences Cellular and Molecular Neuroscience RIPK1 Cell Line Tumor medicine Animals Humans Protein kinase A Protein Kinase Inhibitors 030304 developmental biology MAP kinase kinase kinase Tumor Necrosis Factor-alpha Cell Biology HEK293 Cells Pyrimidines chemistry biology.protein Cancer research Antibody therapy Protein Kinases [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | Cell Death and Disease Cell Death and Disease, Nature Publishing Group, 2015, 6 (5), pp.e1767-e1767. ⟨10.1038/cddis.2015.130⟩ Cell Death and Disease, 2015, 6 (5), pp.e1767-e1767. ⟨10.1038/cddis.2015.130⟩ Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Necroptosis is a form of regulated necrotic cell death mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3. Necroptotic cell death contributes to the pathophysiology of several disorders involving tissue damage, including myocardial infarction, stroke and ischemia-reperfusion injury. However, no inhibitors of necroptosis are currently in clinical use. Here we performed a phenotypic screen for small-molecule inhibitors of tumor necrosis factor-alpha (TNF-α)-induced necroptosis in Fas-associated protein with death domain (FADD)-deficient Jurkat cells using a representative panel of Food and Drug Administration (FDA)-approved drugs. We identified two anti-cancer agents, ponatinib and pazopanib, as submicromolar inhibitors of necroptosis. Both compounds inhibited necroptotic cell death induced by various cell death receptor ligands in human cells, while not protecting from apoptosis. Ponatinib and pazopanib abrogated phosphorylation of mixed lineage kinase domain-like protein (MLKL) upon TNF-α-induced necroptosis, indicating that both agents target a component upstream of MLKL. An unbiased chemical proteomic approach determined the cellular target spectrum of ponatinib, revealing key members of the necroptosis signaling pathway. We validated RIPK1, RIPK3 and transforming growth factor-β-activated kinase 1 (TAK1) as novel, direct targets of ponatinib by using competitive binding, cellular thermal shift and recombinant kinase assays. Ponatinib inhibited both RIPK1 and RIPK3, while pazopanib preferentially targeted RIPK1. The identification of the FDA-approved drugs ponatinib and pazopanib as cellular inhibitors of necroptosis highlights them as potentially interesting for the treatment of pathologies caused or aggravated by necroptotic cell death. |
| Databáze: | OpenAIRE |
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