2. Academic Validation
  3. Development of a RIPK1 degrader to enhance antitumor immunity

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

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. dong.lu@bcm.edu.
  • 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. wangj@bcm.edu.
  • 10 Center for NextGen Therapeutics, Baylor College of Medicine, Houston, TX, USA. wangj@bcm.edu.
  • 11 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. wangj@bcm.edu.
  • # 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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