2. Academic Validation
  3. Discovery of autophagy-tethering compounds as potent NLRP3 degraders for IBD Immunotherapy

Discovery of autophagy-tethering compounds as potent NLRP3 degraders for IBD Immunotherapy

  • Eur J Med Chem. 2024 Sep 5:275:116581. doi: 10.1016/j.ejmech.2024.116581.
Kai Yin 1,  Ziwen Zhang 1,  Yanqing Mo 1,  Hongyu Wu 1,  Zhonglian Cao 2,  Yongxing Xue 1,  Mingrunlin Wang 3,  Wei Guo 4,  Li Feng 5,  Chunchang Zhao 6,  Xianfeng Gu 7
Affiliations

Affiliations

  • 1 School of Pharmacy & Minhang Hospitol, Fudan University, Shanghai 201301, China.
  • 2 Department of Biopharmaceuticals, School of Pharmacy, Fudan University, Shanghai 201301, China.
  • 3 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201301, China.
  • 4 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201301, China. Electronic address: guowei@fudan.edu.cn.
  • 5 School of Pharmacy & Minhang Hospitol, Fudan University, Shanghai 201301, China. Electronic address: feng_li@fudan.edu.cn.
  • 6 School of Chemistry and Molecular Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, 200237, China.
  • 7 School of Pharmacy & Minhang Hospitol, Fudan University, Shanghai 201301, China. Electronic address: xfgu@fudan.edu.cn.
PMID: 38870831 DOI: 10.1016/j.ejmech.2024.116581
Abstract

Nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) constitutes an essential inflammasome sensor protein, pivotal in the orchestration of innate immunity. Given its paramount role, NLRP3 has recently emerged as an enticing therapeutic target for disorders associated with inflammation. In this study, we embarked on the design and synthesis of two series of compounds, endowed with the capacity to induce NLRP3 degradation via autophagy-tethering compounds (ATTECs)-an innovative targeted protein degradation technology. Notably, MC-ND-18 emerged as the most potent agent for effectuating NLRP3 degradation through autophagic mechanisms and concurrently exhibited marked anti-inflammatory efficacy in mice model of dextran sulfate sodium (DSS)-induced colitis. Consequently, we have successfully developed a pioneering NLRP3 protein degrader, offering a novel therapeutic avenue for ameliorating NLRP3-associated pathologies.

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