Design, synthesis, and biological evaluation of RIPK1-targeting PROTACs.

Abstract

Cancer cells can hijack receptor-interacting protein kinase 1 (RIPK1) and exploit its scaffolding function to orchestrate pro-survival signaling and fuel immunosuppressive program. Accordingly, targeting RIPK1 for elimination has emerged as a promising anti-cancer strategy. Based on the RIPK1 inhibitor 4 previously reported by our group, we employed proteolysis targeting chimera (PROTAC) technology and designed a series of RIPK1 degraders. Structure-activity relationship (SAR) study revealed three types of ligands for E3 ligase - cereblon (CRBN), von Hippel-Lindau (VHL) and inhibitor of apoptosis protein (IAP) - demonstrated varied efficacy in RIPK1 degradation of human and mouse cells. The VHL-based compound 18 exhibited potent RIPK1 degradation activity in both human and mouse cellular scenarios. Further biological evaluation confirmed that compound 18 potently induced RIPK1 degradation of I2.1 cells with a DC₅₀ value of 274.4 nM and maintained long-term and dramatic RIPK1 degradation within 72 h. This study provided important insights into future development of RIPK1-PORTACs, and compound 18 was a promising RIPK1 degrader candidate.