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Development of a RIPK1 degrader to enhance antitumor immunity

Author

Listed:
  • Xin Yu

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Dong Lu

    (Baylor College of Medicine)

  • Xiaoli Qi

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Rishi Ram Paudel

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Hanfeng Lin

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Bryan L. Holloman

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Feng Jin

    (Baylor College of Medicine)

  • Longyong Xu

    (Baylor College of Medicine
    The University of Texas M.D. Anderson Cancer Center)

  • Lang Ding

    (Janelia Research Campus)

  • Weiyi Peng

    (University of Houston)

  • Meng C. Wang

    (Janelia Research Campus)

  • Xi Chen

    (Baylor College of Medicine
    The University of Texas M.D. Anderson Cancer Center
    The University of Texas M.D. Anderson Cancer Center)

  • Jin Wang

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

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.

Suggested Citation

  • Xin Yu & Dong Lu & Xiaoli Qi & Rishi Ram Paudel & Hanfeng Lin & Bryan L. Holloman & Feng Jin & Longyong Xu & Lang Ding & Weiyi Peng & Meng C. Wang & Xi Chen & Jin Wang, 2024. "Development of a RIPK1 degrader to enhance antitumor immunity," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-55006-2
    DOI: 10.1038/s41467-024-55006-2
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