Ring closure strategy leads to potent RIPK3 inhibitors.

Abstract

Necroptosis is a form of regulated necrotic cell death that is independent of caspases. Receptor-interacting protein kinase 3 (RIPK3) has been identified as a key regulator for necroptosis, and has been proposed as a potential therapeutic target for the treatment of diseases associated with necroptosis. In this report, we describe the design, synthesis, and evaluation of a series of novel RIPK3 inhibitors. The lead compound 38 exhibited potent activity (EC50=0.42μM) in blocking TNFα, Smac mimetic and z-VAD (TSZ) induced cell death in HT-29cells. Mechanistic studies showed that compound 38 bound to RIPK3 with high affinity (Kd=7.1nM), and inhibited RIPK3 kinase activity in a ADP-Glo functional assay. In addition, compound 38 displayed good selectivity over another necroptosis regulator RIPK1 (Kd=6000nM). Furthermore, compound 38 demonstrated excellent invitro safety profiles with minimal inhibition of CYP isozymes and hERG potassium channel. Lastly, compound 38 efficiently blocked hypothermia and death in mice in the TNFα-induced systemic inflammatory response syndrome model.