Discovery and Development of First-in-Class Cereblon-Recruiting RIPK1 Degraders

Receptor-interacting protein kinase 1 (RIPK1) is a critical regulator of programmed cell death and is implicated in various patholog-ical conditions, particularly in mediating tumor resistance to immune checkpoint inhibitors (ICBs). In this study, we have pioneered the development of a novel cereblon (CRBN)-recruiting RIPK1 degrader, LD5095 , through systematic optimization of linker and CRBN ligand portion. LD5095 demonstrates potent and selective RIPK1 degradation across cell lines, with rapid kinetics and sus-tained degradation over 72h post-washout. Functionally, RIPK1 degradation by LD5095 significantly sensitized Jurkat cells to TNFα-induced apoptosis. Furthermore, LD5095 exhibited favorable pharmacokinetics, including metabolic stability and an ex-tended half-life. Strikingly, in vivo, a single dose of LD5095 achieved durable RIPK1 degradation in xenograft tumors over 6 days. These findings underscore the potential of LD5095 as a chemical probe for studying RIPK1 biology and a promising candi-date for cancer treatment.