The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway mediates anti-microbial innate immunity by inducing the production of type I interferons (IFNs) and inflammatory cytokines upon recognition of microbial DNA. Recent studies reveal that self-DNA from tumors and by-products of genomic instability also activates the cGAS-STING pathway and either promotes or inhibits tumor development[1]. On the one hand, the cGAS-STING axis promotes the clearance of CIN tumors through recruitment of immune cells, thus suppressing tumor progression. On the other hand, the cGAS-STING pathway has been described to be the major regulator in the promotion of metastasis of Chromosomal instability (CIN) tumors[2]. In renal cells of TFAM KO (knockout) mice, aberrant packaging of the mitochondrial DNA (mtDNA) resulted in its cytosolic translocation, activation of the cytosolic cGAS-stimulator of interferon genes (STING) DNA sensing pathway, and thus cytokine expression and immune cell recruitment[3]. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2'3'-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1 -/- mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease[4].
SN-011 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human foreskin fibroblasts (HFFs)
1 µM
6 hours
Inhibited 2'3'-cGAMP-induced IFNB mRNA expression
Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):e2105465118
Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):e2105465118
L929 mouse fibroblasts
1 µM
6 hours
Inhibited HT-DNA-induced Ifnb mRNA expression
Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):e2105465118
Mouse embryonic fibroblasts (MEFs)
1 µM
6 hours
Inhibited STING-triggered Ifnb gene induction
Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):e2105465118
SN-011 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Periodontitis mouse model
Intraperitoneal injection
10 mg/kg
Daily dosing for 7 days
To evaluate the effect of SN-011 on inflammatory response and bone resorption in a periodontitis mouse model. Results showed that SN-011 significantly decreased inflammatory cytokine production and osteoclast formation.
Front Microbiol. 2023 Jun 19;14:1183415
Mice
Trex1−/− mouse model
Intraperitoneal injection
5 mg/kg
Three times per week for one month
Inhibited systemic inflammation and autoimmune markers, prevented death
Proc Natl Acad Sci U S A. 2021 Jun 15;118(24):e2105465118
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