6E11, a highly selective inhibitor of Receptor-Interacting Protein Kinase 1, protects cells against cold hypoxia-reoxygenation injury.
C DelehouzéS Leverrier-PennaF Le CannA ComteM Jacquard-FevaiO DelalandeN DesbanB BaratteI GallaisF FaurezM C BonnetM HautevilleP G GoekjianR ThuillierF FavreauPeter VandenabeeleT HauetM T Dimanche-BoitrelS BachPublished in: Scientific reports (2017)
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.
Keyphrases
- endothelial cells
- protein kinase
- rheumatoid arthritis
- induced apoptosis
- high glucose
- induced pluripotent stem cells
- pluripotent stem cells
- oxidative stress
- left ventricular
- single cell
- heart failure
- vascular endothelial growth factor
- cell death
- endoplasmic reticulum stress
- photodynamic therapy
- aortic valve
- coronary artery
- high resolution
- nitric oxide
- cell therapy
- machine learning
- mass spectrometry
- electronic health record
- resting state
- tyrosine kinase
- cell proliferation
- protein protein
- functional connectivity
- artificial intelligence
- subarachnoid hemorrhage
- pulmonary arterial hypertension