Development of Potent and Selective RIPK1 Degraders with In Vivo Efficacy for Cancer Treatment

Receptor-interacting protein kinase 1 (RIPK1) is a threonine/serine kinase that serves as a critical regulator of immune re-sponses and cell death pathways, functioning through both its catalytic kinase activity and non-catalytic scaffold function. The scaffold function of RIPK1 contributes to both intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs), making it a compelling therapeutic target for enhancing cancer immunotherapy. Recent studies have highlighted RIPK1’s potential as a key modulator for improving the efficacy of immune-stimulatory therapies, such as ICBs and radio-therapy. In this study, we have developed a highly potent and selective RIPK1 degrader. Our degrader demonstrated signifi-cant tumor growth suppression when combined with X-ray radiotherapy (XRT), achieving enhanced therapeutic efficacy without adverse effects on body weight. These findings underscore the potential of RIPK1 degradation as a novel approach to augment radiotherapy and advance cancer immunotherapy strategies.