Sibiriline, a new small chemical inhibitor of receptor-interacting protein kinase 1, prevents immune-dependent hepatitis

Abstract : Necroptosis is a regulated form of cell death involved in several disease models including in particular liver diseases. Receptor-interacting protein kinases, RIPK1 and RIPK3, are the main serine/threonine kinases driving this cell death pathway. We screened a noncommercial, kinase-focused chemical library which allowed us to identify Sibiriline as a new inhibitor of necroptosis induced by tumor necrosis factor (TNF) in Fas-associated protein with death domain (FADD)-deficient Jurkat cells. Moreover, Sib inhibits necroptotic cell death induced by various death ligands in human or mouse cells while not protecting from caspase-dependent apoptosis. By using competition binding assay and recombinant kinase assays, we demonstrated that Sib is a rather specific competitive RIPK1 inhibitor. Molecular docking analysis shows that Sib is trapped closed to human RIPK1 adenosine triphosphate-binding site in a relatively hydrophobic pocket locking RIPK1 in an inactive conformation. In agreement with its RIPK1 inhibitory property, Sib inhibits both TNF-induced RIPK1-dependent necroptosis and RIPK1-dependent apoptosis. Finally, Sib protects mice from concanavalin A-induced hepatitis. These results reveal the small-molecule Sib as a new RIPK1 inhibitor potentially of interest for the treatment of immune-dependent hepatitis. © 2017 Federation of European Biochemical Societies
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Article dans une revue
FEBS Journal, 2017, 284 (18), pp.3050-3068. 〈10.1111/febs.14176〉
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616420
Contributeur : Xavier Chard-Hutchinson <>
Soumis le : vendredi 13 octobre 2017 - 16:12:46
Dernière modification le : mardi 16 janvier 2018 - 14:50:26

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F. Le Cann, C. Delehouzé, S. Leverrier-Penna, A. Filliol, A. Comte, et al.. Sibiriline, a new small chemical inhibitor of receptor-interacting protein kinase 1, prevents immune-dependent hepatitis. FEBS Journal, 2017, 284 (18), pp.3050-3068. 〈10.1111/febs.14176〉. 〈hal-01616420〉

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