Development of a RIPK1 degrader to enhance antitumor immunity
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.
Authors
- Meng Carla Wang (ORCID: https://orcid.org/0000-0002-5898-6007)
- Feng Jin (ORCID: https://orcid.org/0000-0002-9099-9318)
- Longyong Xu (ORCID: https://orcid.org/0000-0002-8574-4062)
- Hanfeng Lin (ORCID: https://orcid.org/0000-0002-3172-5616)
- Weiyi Peng (ORCID: https://orcid.org/0000-0002-7785-6240)
- Bryan L. Holloman (ORCID: https://orcid.org/0000-0002-9891-9001)
- Jin Wang (ORCID: https://orcid.org/0000-0003-3625-7919)
- Xin Yu (ORCID: https://orcid.org/0000-0002-8718-0715)
- Dong Lu (ORCID: https://orcid.org/0000-0002-9919-6378)
- Xi Chen (ORCID: https://orcid.org/0000-0002-7995-6202)
- Rishi R. Paudel (ORCID: https://orcid.org/0000-0002-8468-2381)
- Xiaoli Qi (ORCID: https://orcid.org/0000-0002-7881-3365)
- Lang Ding (ORCID: https://orcid.org/0000-0002-5365-9445)
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Baylor College of Medicine (US)
- Janelia Research Campus (US)
- University of Houston (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-16
- DOI
- https://doi.org/10.1038/s41467-024-55006-2
- Citations
- 21
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 4.91
Funders
- Cancer Prevention and Research Institute of Texas
- National Institutes of Health
- National Cancer Institute