Development of a RIPK1 degrader to enhance antitumor immunity

  • Nat Commun. 2024 Dec 16;15(1):10683. doi: 10.1038/s41467-024-55006-2.
Xin Yu  #  1  2 ,  Dong Lu  #  3 ,  Xiaoli Qi  1  2 ,  Rishi Ram Paudel  1  2 ,  Hanfeng Lin  1  2 ,  Bryan L Holloman  1  2 ,  Feng Jin  1 ,  Longyong Xu  4  5 ,  Lang Ding  6 ,  Weiyi Peng  7 ,  Meng C Wang  6 ,  Xi Chen  4  5  8 ,  Jin Wang  9  10  11
Affiliations
  • 1. The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
  • 2. Center for NextGen Therapeutics, Baylor College of Medicine, Houston, TX, USA.
  • 3. The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 5. Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
  • 6. Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA.
  • 7. Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
  • 8. James P. Allison Institute, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
  • 9. The Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 10. Center for NextGen Therapeutics, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 11. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • # Contributed equally.
PMID: 39681571 DOI: 10.1038/s41467-024-55006-2
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.

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