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

Le Cann, Fabienne, Delehouzé, Claire, Leverrier-Penna, Sabrina, Filliol, Aveline, Comte, Arnaud, Delalande, Olivier, Desban, Nathalie, Baratte, Blandine, Gallais, Isabelle, Piquet-Pellorce, Claire, Faurez, Florence, Bonnet, Marion ORCID:, Mettey, Yvette, Goekjian, Peter, Samson, Michel, Vandenabeele, Peter, Bach, Stéphane and Dimanche-Boitrel, Marie-Thérèse 2017. Sibiriline, a new small chemical inhibitor of receptor-interacting protein kinase 1, prevents immune-dependent hepatitis. FEBS Journal 284 (18) , pp. 3050-3068. 10.1111/febs.14176

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Wiley-Blackwell
ISSN: 1742-464X
Date of First Compliant Deposit: 11 August 2017
Date of Acceptance: 13 July 2017
Last Modified: 06 May 2023 05:45

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