Targeted Degradation of Receptor-Interacting Protein Kinase 1 to Modulate the Necroptosis Pathway

  • ACS Pharmacol Transl Sci. 2024 Oct 15;7(11):3518-3526. doi: 10.1021/acsptsci.4c00421.
Hiroyuki Inuzuka  1 ,  Chao Qian  2 ,  Yihang Qi  1 ,  Yan Xiong  2 ,  Chaoyu Wang  1 ,  Zhen Wang  1 ,  Dingpeng Zhang  1 ,  Can Zhang  3 ,  Jian Jin  2 ,  Wenyi Wei  1
Affiliations
  • 1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 2. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 3. Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.
PMID: 39539258 DOI: 10.1021/acsptsci.4c00421
Abstract

Necroptosis is a highly regulated form of necrotic cell death that plays an essential role in pathogen defense and tissue homeostasis. Abnormal regulation of the necroptotic pathway has been implicated in the pathogenesis of various human diseases, including Cancer, inflammatory, and neurodegenerative diseases. Receptor-interacting protein kinase 1 (RIPK1) serves as a crucial regulator of the necroptotic signaling pathway and has been identified as a potential therapeutic target. Mechanistically, RIPK1 serves as both a protein kinase and a scaffolding protein, fulfilling its dual function through a combination of kinase activity-dependent and kinase activity-independent mechanisms. Thus, employing a targeted RIPK1 knockdown strategy is a highly effective means of inhibiting RIPK1 functions. To achieve a targeted RIPK1 knockdown, we generated a RIPK1-PROTAC, MS2031, by connecting the ZB-R-55 RIPK1 binder to the VHL ligand, thereby recruiting the CUL2-RING-VHL (CRL2VHL) E3 ubiquitin Ligase complex for targeted degradation of RIPK1 through the 26S Proteasome. Notably, MS2031 treatment effectively reduced the abundance of RIPK1 protein in the nanomolar range in various cell lines we examined, including HT-29 and T47D cells, and modulated the Necroptosis signaling pathway. These results suggest that MS2031 may hold potential for the treatment of human diseases resulting from aberrant regulation of RIPK1.

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