2. Academic Validation
  3. Discovery of Sibiriline derivatives as novel receptor-interacting protein kinase 1 inhibitors

Discovery of Sibiriline derivatives as novel receptor-interacting protein kinase 1 inhibitors

  • Eur J Med Chem. 2023 Mar 15;250:115190. doi: 10.1016/j.ejmech.2023.115190.
Ningjie Cui 1,  Shang Li 1,  Yonglei Zhang 1,  Fucheng Yin 1,  Xinye Chen 1,  Zhongwen Luo 1,  Siyuan Wan 1,  Xinxin Li 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, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: cpu_lykong@126.com.
  • 3 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: xbwang@cpu.edu.cn.
PMID: 36801518 DOI: 10.1016/j.ejmech.2023.115190
Abstract

Receptor-interacting protein kinase 1 (RIPK1), a vital protein of the Necroptosis pathway, plays a pivotal role in various inflammatory diseases. Sibiriline has been reported to be a potent ATP-competitive RIPK1 Inhibitor, but its anti-necroptotic effects are limited. A series of structural analogues of Sibiriline were synthesized and evaluated for their anti-necroptotic activity. Comprehensive structure-activity relationship (SAR) was performed to left azaindole and right substituents of benzene of Sibiriline, respectively. The optimal compound KWCN-41, specifically inhibiting cell Necroptosis but not Apoptosis, protects cell survival by blocking the necroptotic pathway, which inhibits the phosphorylation of essential proteins of the Necroptosis. It also prevented the development of inflammation and reduced the level of inflammatory factors in mice. KWCN-41 is expected to be a lead compound for further studies in inflammatory diseases.

Keywords

Cell death; Inflammation; Necroptosis; Receptor-interacting protein kinase 1; Sibiriline.

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