Design, synthesis, and evaluation of thiazolecarboxamide derivatives as stimulator of interferon gene inhibitors.
Mol Divers
; 2024 Apr 29.
Article
em En
| MEDLINE
| ID: mdl-38683489
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.
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MEDLINE
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En
Ano de publicação:
2024
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Article