Discovery of Sibiriline derivatives as novel receptor-interacting protein kinase 1 inhibitors.

Receptor-interacting protein kinase 1 (RIPK1), a vital protein of the necroptosis pathway, plays a pivotal role in various inflammatory diseases. Sibiriline has been reported to be a potent ATP-competitive RIPK1 inhibitor, but its anti-necroptotic effects are limited. A series of structural analogues of Sibiriline were synthesized and evaluated for their anti-necroptotic activity. Comprehensive structure-activity relationship (SAR) was performed to left azaindole and right substituents of benzene of Sibiriline, respectively. The optimal compound KWCN-41, specifically inhibiting cell necroptosis but not apoptosis, protects cell survival by blocking the necroptotic pathway, which inhibits the phosphorylation of essential proteins of the necroptosis. It also prevented the development of inflammation and reduced the level of inflammatory factors in mice. KWCN-41 is expected to be a lead compound for further studies in inflammatory diseases.