Development of Potent and Selective RIPK1 Degraders Targeting Its Nonenzymatic Function for Cancer Treatment
Year: 2025
Type: article
Abstract: 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.
Source: Journal of Medicinal Chemistry
Institution: University of Wisconsin–Madison
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Wisconsin Alumni Research Foundation, University of Wisconsin-Madison, National Institutes of Health, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G1226907486, Acquisition of a High-Field Dual Source FTICR-MS for Pharmaceutical Research, G2118924489, G2388130288, G2922573454, G3055837027, G3418984644, Acquisition of a High Resolution High Speed MALDI Mass Spectrometer for Biomedical Research at UW-Madison, Acquisition of a Dual-Source, High-Performance, Ion Mobility, Quadrupole Time-of-Flight Mass Spectrometry System for Biomedical Research at UW-Madison, G822836364, G9000231773, National Center for Quantitative Biology of Complex Systems
OpenAlex ID: W4412464727