Sibiriline : une nouvelle molécule inhibant la mort cellulaire par nécrose
La Sibiriline, une nouvelle molécule synthétique inhibant la mort cellulaire par nécrose régulée vient d'être identifiée par la Plateforme KISSf (Biogenouest/IBISA/cancéropôle grand-ouest) en collaboration avec l'IRSET Rennes. Ce travail a été mené à partir de sa collection qui compte plus de 18 000 molécules. Les applications en thérapie humaine sont nombreuses et concernent notamment les conséquences de chocs ischémiques. Dans cet article, la molécule a été testée in vivo et a protégé significativement la souris d’une forme d’hépatite.
Résumé (anglais)
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
Référence
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.
http://onlinelibrary.wiley.com/doi/10.1111/febs.14176/abstract