Publication Date
12-16-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-55006-2
PMID
39681571
PMCID
PMC11649918
PubMedCentral® Posted Date
12-16-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Receptor-Interacting Protein Serine-Threonine Kinases, Female, Mice, Mice, Inbred C57BL, Humans, Cell Line, Tumor, Proteolysis, Immunotherapy, Lymphocytes, Tumor-Infiltrating, Immune Checkpoint Inhibitors, Neoplasms, Programmed Cell Death 1 Receptor, Small molecules, Cancer immunotherapy, Drug discovery and development
Abstract
The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports a RIPK1 degrader that serves as a chemical probe for investigating the scaffolding functions of RIPK1 and as a potential therapeutic agent to enhance tumor responses to ICBs therapy.
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Biological Phenomena, Cell Phenomena, and Immunity Commons, Life Sciences Commons, Medical Cell Biology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Medical Specialties Commons
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