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

C. Delehouzé (1) , S. Leverrier-Penna (2) , F. Le Cann (2) , A. Comte (3) , M. Jacquard-Fevai (4, 5) , O. Delalande (6) , N. Desban (1) , B. Baratte (1) , I. Gallais (2) , F. Faurez (2) , M. C. C Bonnet (2) , M. Hauteville (7) , P. G. Goekjian (3) , R. Thuillier (8, 9, 5) , F. Favreau (9, 5) , P. Vandenabeele (10) , T. Hauet (9, 11) , Marie-Thérèse Dimanche-Boitrel (2) , S. Bach (1) , & S Bach

1 P3H - Phophorylation de protéines et Pathologies Humaines
2 Irset - Institut de recherche en santé, environnement et travail
3 CO2GLYCO - Chimie Organique 2-Glycochimie
4 Université de Poitiers - Faculté de Médecine et de Pharmacie
5 IRTOMIT - Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques
6 IGDR - Institut de Génétique et Développement de Rennes
7 UCBL - Université Claude Bernard Lyon 1
8 CHU Poitiers - Centre hospitalier universitaire de Poitiers
9 GenESI - Génétique, Expérimentation et Système Innovants
10 UGENT - Universiteit Gent = Ghent University
11 FHU SUPORT - Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation

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-alpha (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.

Keywords: Necroptosis; Necroptosis

Domains: Chemical Sciences; Medicinal Chemistry

C. Delehouzé, S. Leverrier-Penna, F. Le Cann, A. Comte, M. Jacquard-Fevai, et al.. 6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury. Scientific Reports, 2017, 7 (1), pp.12931. ⟨10.1038/s41598-017-12788-4⟩. ⟨hal-01616456⟩