2. Academic Validation
  3. Design, synthesis, and evaluation of thiazolecarboxamide derivatives as stimulator of interferon gene inhibitors

Design, synthesis, and evaluation of thiazolecarboxamide derivatives as stimulator of interferon gene inhibitors

  • Mol Divers. 2024 Apr 29. doi: 10.1007/s11030-024-10860-6.
Zechen Jin # 1 2,  Yan Zhang # 3,  Xin Luo 3 4,  Meiyu Geng 3 5,  Wenhu Duan 1 2 5,  Zuoquan Xie 6,  Hefeng Zhang 7
Affiliations

Affiliations

  • 1 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
  • 2 School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xian Lin Road, Nanjing, 210023, China.
  • 5 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China. zqxie@simm.ac.cn.
  • 7 Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China. zhanghefeng1@simm.ac.cn.
  • # Contributed equally.
PMID: 38683489 DOI: 10.1007/s11030-024-10860-6
Abstract

Stimulator of interferon gene (STING) plays critical roles in the cytoplasmic DNA-sensing pathway and in the induction of inflammatory response. Aberrant cytoplasmic DNA accumulation and STING activation are implicated in numerous inflammatory and autoimmune diseases. Here, we reported the discovery of a series of thiazolecarboxamide-based STING inhibitors through a molecular planarity/symmetry disruption strategy. The privileged compound 15b significantly inhibited STING signaling and suppressed immune-inflammatory cytokine levels in both human and murine cells. In vivo experiments demonstrated 15b effectively ameliorated immune-inflammatory cytokines upregulation in MSA-2-stimulated and Trex1-D18N mice. Furthermore, compound 15b exhibited enhanced efficacy in suppressing interferon-stimulated gene 15 (ISG15), a critical positive feedback regulator of STING. Overall, compound 15b deserves further development for the treatment of STING-associated inflammatory and autoimmune diseases.

Keywords

Inflammation; Inhibitor; Interferon-stimulated gene 15; Stimulator of interferon gene; Thiazolecarboxamide.

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