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Sci Rep. 2017 Oct 10;7(1):12931. doi: 10.1038/s41598-017-12788-4.

6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury.

Author information

1
Sorbonne Universités, UPMC Univ Paris 06, CNRS USR3151, Protein Phosphorylation and Human Disease Laboratory, Station Biologique, F-29688, Roscoff, France.
2
INSERM UMR 1085, Institut de Recherche sur la Santé, l'Environnement et le Travail, F-35043, Rennes, France.
3
Biosit UMS 3080, Université de Rennes 1, F-35043, Rennes, France.
4
Molecular Signaling and Cell Death Unit, VIB Inflammation Research Center, Ghent, Belgium.
5
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
6
Université de Lyon, CNRS UMR 5246, ICBMS, Chimiothèque, Université Claude Bernard Lyon 1, F-69622, Villeurbanne, France.
7
Inserm, U1082, Poitiers, France.
8
CHU de Poitiers, Service de Biochimie, Poitiers, France.
9
Université de Poitiers, Faculté de Médecine et de Pharmacie, Poitiers, France.
10
Fédération Hospitalo-Universitaire SUPORT, Poitiers, France.
11
IBiSA Plateforme 'MOPICT', Institut national de la recherche agronomique, Unité expérimentale Génétique, expérimentations et systèmes innovants, Domaine Expérimental du Magneraud, Surgères, France.
12
CNRS UMR 6290, Institut de Génétique et Développement de Rennes, Université de Rennes 1, F-35043, Rennes, France.
13
Division of Infection & Immunity, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom.
14
Laboratoire de Biochimie Analytique et Synthèse Bioorganique, Université de Lyon, Université Claude Bernard Lyon 1, F-69622, Villeurbanne, France.
15
Université de Lyon, CNRS UMR 5246, ICBMS, Laboratoire Chimie Organique 2-Glycosciences, Université Claude Bernard Lyon 1, F-69622, Villeurbanne, France.
16
INSERM UMR 1085, Institut de Recherche sur la Santé, l'Environnement et le Travail, F-35043, Rennes, France. marie-therese.boitrel@univ-rennes1.fr.
17
Biosit UMS 3080, Université de Rennes 1, F-35043, Rennes, France. marie-therese.boitrel@univ-rennes1.fr.
18
Sorbonne Universités, UPMC Univ Paris 06, CNRS USR3151, Protein Phosphorylation and Human Disease Laboratory, Station Biologique, F-29688, Roscoff, France. bach@sb-roscoff.fr.

Abstract

Necroptosis is a programmed cell death pathway that has been shown to be of central pathophysiological relevance in multiple disorders (hepatitis, brain and cardiac ischemia, pancreatitis, viral infection and inflammatory diseases). Necroptosis is driven by two serine threonine kinases, RIPK1 (Receptor Interacting Protein Kinase 1) and RIPK3, and a pseudo-kinase MLKL (Mixed Lineage Kinase domain-Like) associated in a multi-protein complex called necrosome. In order to find new inhibitors for use in human therapy, a chemical library containing highly diverse chemical structures was screened using a cell-based assay. The compound 6E11, a natural product derivative, was characterized as a positive hit. Interestingly, this flavanone compound: inhibits necroptosis induced by death receptors ligands TNF-α (Tumor Necrosis Factor) or TRAIL (TNF-Related Apoptosis-Inducing Ligand); is an extremely selective inhibitor, among kinases, of human RIPK1 enzymatic activity with a nM Kd; has a non-ATP competitive mode of action and a novel putative binding site; is weakly cytotoxic towards human primary blood leukocytes or retinal pigment epithelial cells at effective concentrations; protects human aortic endothelial cells (HAEC) from cold hypoxia/reoxygenation injury more effectively than necrostatin-1 (Nec-1) and Nec-1s. Altogether, these data demonstrate that 6E11 is a novel potent small molecular inhibitor of RIPK1-driven necroptosis.

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