2. Academic Validation
  3. Discovery of phenylisoxazolidine analogs targeting receptor interacting protein kinase 1 with anti-inflammatory activity

Discovery of phenylisoxazolidine analogs targeting receptor interacting protein kinase 1 with anti-inflammatory activity

  • Eur J Med Chem. 2025 Jun 5:290:117530. doi: 10.1016/j.ejmech.2025.117530.
Liangliang Ma 1,  Yonglei Zhang 1,  Zhongwen Luo 1,  Long Zheng 1,  Yuhan Jiang 1,  Meiting Zou 1,  Yiwei Zheng 1,  Lingyi Kong 2,  Xiaobing Wang 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
  • 2 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.
  • 3 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: xbwang@cpu.edu.cn.
PMID: 40153932 DOI: 10.1016/j.ejmech.2025.117530
Abstract

Receptor Interacting Protein Kinase1 (RIPK1) is a key regulator of Necroptosis and plays an important role in various inflammatory signaling and cell death processes. GSK963 has been reported to inhibit RIPK1 with limited anti-necroptotic effect. We designed and prepared a series of phenylisoxazolidine analogs based on GSK963 to improve their anti-necroptotic activity. After several turns of structure activity relationship (SAR) studies, compound 22, encoded with KWML-22, was found to have good anti-necroptotic activity (EC50 = 30.0 nM) and enzymatic activity (IC50 = 6.9 nM) against RIPK1. In a TNF-α-induced inflammation in vivo model, a dose of 10 mg/kg protected mice from hypothermia and death. Our results suggest that 22 is a promising lead compound for the study of inflammatory diseases.

Keywords

Inflammatory; Necroptosis; RIPK1; TNF-α.

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