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Sibiriline, a new small chemical inhibitor of receptor‐interacting protein kinase 1, prevents immune‐dependent hepatitis
Author(s) -
Le Cann Fabienne,
Delehouzé Claire,
LeverrierPenna Sabrina,
Filliol Aveline,
Comte Arnaud,
Delalande Olivier,
Desban Nathalie,
Baratte Blandine,
Gallais Isabelle,
PiquetPellorce Claire,
Faurez Florence,
Bonnet Marion,
Mettey Yvette,
Goekjian Peter,
Samson Michel,
Vandenabeele Peter,
Bach Stéphane,
DimancheBoitrel MarieThérèse
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14176
Subject(s) - ripk1 , necroptosis , fadd , programmed cell death , kinase , jurkat cells , microbiology and biotechnology , biology , protein kinase a , chemistry , apoptosis , cancer research , biochemistry , caspase , immune system , immunology , t cell
Necroptosis is a regulated form of cell death involved in several disease models including in particular liver diseases. Receptor‐interacting protein kinases, RIPK 1 and RIPK 3, 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 RIPK 1 inhibitor. Molecular docking analysis shows that Sib is trapped closed to human RIPK 1 adenosine triphosphate‐binding site in a relatively hydrophobic pocket locking RIPK 1 in an inactive conformation. In agreement with its RIPK 1 inhibitory property, Sib inhibits both TNF ‐induced RIPK 1‐dependent necroptosis and RIPK 1‐dependent apoptosis. Finally, Sib protects mice from concanavalin A‐induced hepatitis. These results reveal the small‐molecule Sib as a new RIPK 1 inhibitor potentially of interest for the treatment of immune‐dependent hepatitis.