2. Academic Validation
  3. Discovery of novel Bis-amide analogue ST12 for the treatment of inflammatory bowel diseases (IBD) by inhibiting NLRP3 inflammasome activation

Discovery of novel Bis-amide analogue ST12 for the treatment of inflammatory bowel diseases (IBD) by inhibiting NLRP3 inflammasome activation

  • Bioorg Chem. 2025 Jun 1:159:108402. doi: 10.1016/j.bioorg.2025.108402.
Zhiqiang Sun 1,  Qinru Zang 1,  Chenglong Xu 1,  Xuewen Zhang 1,  Zhenghui Kang 2,  Yushe Yang 3,  Ling Li 4,  Jianjun Chen 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China. Electronic address: kangzhenghui@simm.ac.cn.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ysyang@simm.ac.cn.
  • 4 The Eighth Affiliated Hospital Sun Yat-sen University, 3025 Shennan Middle Road, Shenzhen 518000, China. Electronic address: 931402843@qq.com.
  • 5 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jchen21@smu.edu.cn.
PMID: 40154236 DOI: 10.1016/j.bioorg.2025.108402
Abstract

Herein, we designed and synthesized a series of novel bis-amide small molecule anti-inflammatory agents, among them, compound ST12 showed most potent anti-inflammatory activity. ST12 effectively inhibited the production of nitric oxide (NO) (inhibition rate of 52.67 ± 0.03 % at 10 μM) and downregulated the mRNA levels of proinflammatory cytokines iNOS, IL-6, IL-1β and TNF-α in lipopolysaccharide (LPS) induced RAW264.7 cells. Furthermore, mechanism studies suggest that compound ST12 exerted anti-inflammatory effects by inhibiting the activation of the NLRP3 inflammasome. Importantly, ST12 effectively ameliorated DSS-induced colitis in vivo. Taken together, ST12 is worthy of further investigation as a small molecule anti-inflammatory agent for treatment of inflammatory bowel diseases (IBD).

Keywords

Anti-inflammatory agents; Inflammatory bowel diseases (IBD); NLRP3 inflammasome; Nitric oxide (NO).

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