2. Academic Validation
  3. Development of Potent and Selective RIPK1 Degraders Targeting Its Nonenzymatic Function for Cancer Treatment

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

  • J Med Chem. 2025 Jul 24;68(14):15120-15136. doi: 10.1021/acs.jmedchem.5c01340.
Zhen Zhang 1,  Chunrong Li 1,  Nina J Hawkins 1,  Ramesh Mudududdla 1,  Yiming Nie 1,  Peng-Kai Liu 2,  Penghsuan Huang 3,  Natalia M Del Rio 4,  Hao Chang 5,  Matthew E Brown 4,  Lingjun Li 1 2 3,  Weiping Tang 1 3
Affiliations

Affiliations

  • 1 Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison Madison, Wisconsin 53705, United States.
  • 2 Biophysics Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.
  • 3 Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States.
  • 4 Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53792, United States.
  • 5 Department of Dermatology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.
PMID: 40665578 DOI: 10.1021/acs.jmedchem.5c01340
Abstract

Receptor-interacting protein kinase 1 (RIPK1) is a threonine/serine kinase that serves as a critical regulator of immune responses and cell death pathways, functioning through both its kinase activity and nonenzymatic scaffolding function. The scaffolding function of RIPK1 contributes to both intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs), making it a compelling therapeutic target for Cancer treatment. Recent studies have highlighted RIPK1's potential as a key modulator for improving the efficacy of immune-stimulatory therapies, such as ICBs and X-ray radiotherapy (XRT). In this study, we have developed a highly potent and selective RIPK1 degrader. When combined with XRT, the degrader significantly suppressed tumor growth, achieving enhanced therapeutic efficacy without apparent adverse effects. In contrast, the RIPK1 Inhibitor showed no notable therapeutic effect. These findings underscore the potential of targeting RIPK1 degradation, specifically its nonenzymatic function, as a novel strategy to augment the effects of radiotherapy.

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