Year: 2024
Type: article
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.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: G1160407362, CyTOF XT with Hyperion XTi platform, Development of First-in-Class RIPK1 Degraders to Improve Cancer Immunotherapies, RIP PROTACs as a Novel Immunotherapy Sensitizer to Treat Colorectal Cancer, Advanced Multiparameter Cytometry and Cell Sorting Core, G6993648036, Reversible Covalent BTK Degraders as the Next Generation Targeted Therapy to Treat B-cell Malignancies, G742290332, G7837447426, G8836850136, G9000124642, G9000240210, Baylor College of Medicine Cancer Center - Cancer Center Support Grant
OpenAlex ID: W4405419978