The article describing the in vivo effect of Sibiriline, a new inhibitor of regulated necrosis, on Concanavalin A-induced hepatitis is online.
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 non-commercial kinase-focused chemical library allowed us to identify Sibiriline as new inhibitor of necroptosis induced by 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 ATP-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
Le Cann F., Delehouzé C., Penna-Leverrier S., Filliol A., Comte A., Delalande O., Desban N., Baratte B., Gallais I., Piquet-Pellorce C., Faurez F., Bonnet M., Mettey Y., Goekjian P., Samson M., Vandenabeele P., Bach S.* and Dimanche-Boitrel M-T.* 2017. Sibiriline, a new small chemical inhibitor of Receptor-Interacting Protein Kinase 1, prevents immune-dependent hepatitis. FEBS Journal, doi: 10.1111/febs.14176.