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Development of Potent and Selective RIPK1 Degraders Targeting Its Nonenzymatic Function for Cancer Treatment

Zhen Zhang1, Chunrong Li1, Nina J Hawkins1

  • 1Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison Madison, Wisconsin 53705, United States.

Journal of Medicinal Chemistry
|July 16, 2025
PubMed

Insights

Targeting Receptor-Interacting Protein Kinase 1 (RIPK1) degradation, not inhibition, enhances cancer radiotherapy efficacy. A novel RIPK1 degrader combined with X-ray radiotherapy suppressed tumor growth effectively, showing promise for novel cancer treatments.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Receptor-interacting protein kinase 1 (RIPK1) is crucial for immune responses and cell death.
  • RIPK1's scaffolding function confers resistance to immune checkpoint blockades (ICBs), presenting a therapeutic target in cancer.
  • RIPK1 modulates efficacy of immune-stimulatory therapies like ICBs and X-ray radiotherapy (XRT).

Purpose of the Study:

  • To investigate the therapeutic potential of targeting RIPK1 degradation in combination with XRT.
  • To evaluate a novel RIPK1 degrader for cancer treatment efficacy.

Main Methods:

  • Development of a potent and selective RIPK1 degrader.
  • Combination therapy of the RIPK1 degrader with X-ray radiotherapy (XRT) in preclinical cancer models.
  • Assessment of tumor growth suppression and therapeutic efficacy.

Main Results:

  • The RIPK1 degrader combined with XRT significantly suppressed tumor growth.
  • Enhanced therapeutic efficacy was observed without apparent adverse effects.
  • A RIPK1 inhibitor showed no notable therapeutic effect, highlighting the importance of degradation over inhibition.

Conclusions:

  • Targeting RIPK1 degradation, particularly its nonenzymatic function, is a promising strategy to enhance radiotherapy outcomes.
  • RIPK1 degradation offers a novel approach to augment the effects of XRT in cancer treatment.
  • Selective RIPK1 degradation demonstrates superior therapeutic potential compared to RIPK1 inhibition in combination with XRT.

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