Development of Potent and Selective RIPK1 Degraders Targeting Its Nonenzymatic Function for Cancer Treatment.

Receptor-interacting protein kinase 1 (RIPK1) is a threonine/serine kinase that serves as a critical regulator of immune responses and cell death pathways, functioning through both its kinase activity and nonenzymatic scaffolding function. The scaffolding function of RIPK1 contributes to both intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs), making it a compelling therapeutic target for cancer treatment. Recent studies have highlighted RIPK1's potential as a key modulator for improving the efficacy of immune-stimulatory therapies, such as ICBs and X-ray radiotherapy (XRT). In this study, we have developed a highly potent and selective RIPK1 degrader. When combined with XRT, the degrader significantly suppressed tumor growth, achieving enhanced therapeutic efficacy without apparent adverse effects. In contrast, the RIPK1 inhibitor showed no notable therapeutic effect. These findings underscore the potential of targeting RIPK1 degradation, specifically its nonenzymatic function, as a novel strategy to augment the effects of radiotherapy.