Abstract
Targeting RIPK1,2,3 to combat inflammation.
Highlights
RIPK1 and RIPK3 kinase activities have been linked to the process of regulated necrotic cell death or “necroptosis”, which contributes to a variety of necrotic injuries in vivo
Three independent studies by our labs and the laboratory of Dr Giulio Superti-Furga have suggested new opportunities for pan-Receptor Interacting Protein Kinases (RIPKs) targeting by small molecule inhibitors [5,6,7]
Cellular analyses indicated that ponatinib inhibited NOD1/2, TLR4 and TNF-induced inflammation and cell death through targeting RIPKs at low nanomolar concentrations
Summary
RIPK1 and RIPK3 kinase activities have been linked to the process of regulated necrotic cell death or “necroptosis”, which contributes to a variety of necrotic injuries in vivo (reviewed further in [1]). Three independent studies by our labs and the laboratory of Dr Giulio Superti-Furga have suggested new opportunities for pan-RIPK targeting by small molecule inhibitors [5,6,7]. As a starting point, screening of clinical kinase inhibitors identified the third generation Bcr-Abl inhibitor ponatinib as a low nanomolar inhibitor of cellular necroptosis. Subsequent in vitro experiments revealed inhibition of recombinant RIPK1, RIPK2 and RIPK3 by this molecule [5,6,7].
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