2. Academic Validation
  3. Discovery of a novel Thiazole amide inhibitor of Inflammasome and Pyroptosis pathways

Discovery of a novel Thiazole amide inhibitor of Inflammasome and Pyroptosis pathways

  • Bioorg Chem. 2025 Jun 15:160:108477. doi: 10.1016/j.bioorg.2025.108477.
Zhen Dai 1,  Ke Wang 2,  Chenli Bai 2,  Yong Li 3,  Quanwei Yu 4,  Zhiping Chen 2,  Jihong Liao 2,  Jianjun Ding 5,  Yuxi Wang 6
Affiliations

Affiliations

  • 1 Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, Sichuan, China. Electronic address: daizhen15@163.com.
  • 2 Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, Sichuan, China.
  • 3 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, IATTI, Chongqing University of Arts and Sciences, Chongqing 402160, China. Electronic address: 18708168370@163.com.
  • 4 Targeted Tracer Research and development laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 5 School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Nanjing, China.
  • 6 Targeted Tracer Research and development laboratory, Institute of Respiratory Health, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: yuxiwang@scu.edu.cn.
PMID: 40252370 DOI: 10.1016/j.bioorg.2025.108477
Abstract

Upon the activation of inflammasomes, inflammatory caspases cleave and activate gasdermin D (GSDMD), leading to pore formation that causes cell membrane rupture and amplifies downstream inflammatory responses. Dysregulated inflammasome activation and Pyroptosis signaling pathways are implicated in numerous inflammatory diseases. In our work, a set of novel thiazole amide compounds with inhibitory activity against NLRP3 inflammasome-induced Pyroptosis was identified. Of all the compounds tested, compound 21 demonstrated the most potent anti-pyroptotic effects. It suppressed GSDMD cleavage and decreased IL-1β and Lactate Dehydrogenase (LDH) release in a concentration-dependent manner. Compound 21 bound to NLRP3 protein and increased the thermal stability of NLRP3 concentration-dependently. The molecular docking and dynamics simulations revealed that compound 21 binds to the NLRP3 protein's active site, suppressing inflammasome activation. Further investigations showed that compound 21 also partially blocked upstream NF-κB signaling and downstream GSDMD N-terminal domain (GSDMD-NT) oligomerization, which explains its broad inhibitory effects on Pyroptosis driven by multiple inflammasomes. Overall, this study presents a promising thiazole amide compound with inhibitory activity against inflammasome activation and subsequent Pyroptosis, warranting further exploration.

Keywords

GSDMD; Inflammasome; Inhibitor; NLRP3; Pyroptosis.

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