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
  • 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. [email protected].
  • 7. Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China. [email protected].
  • # 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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