Synthesis and characterization of potent RIPK3 inhibitors based on a tricyclic scaffold.

Abstract

Necroptosis is an important form of regulated cell death involved in inflammatory diseases, degenerative diseases and cancer. RIPK3 is an interesting target for intervention of necroptosis-associated diseases.Herein the authors report the synthesis of a series RIPK3 inhibitors under the guidance of structure-based drug design which leads to the identification of compound.Compoundpotently rescued human and mouse cells from necroptotic stimuli TNF-α, Smac mimetic, z-VAD and LPS + z-VAD, displayed high affinity to RIPK3 (Kd = 14 nM) but no observable affinity to RIPK1 and inhibited RIPK3 kinase function. Importantly, compoundsignificantly alleviated TNF-induced systemic inflammatory response syndrome in the mouse model.These results support compoundas a prototype RIPK3 inhibitor for lead optimization.