DUN99845 was reported as a STING inhbiitor, which inhibited the activation of the STING signal pathway and to prevent or treat a STING-mediated disease.
The cGAS-STING signalling axis, comprising the synthase for the second messenger cyclic GMP-AMP (cGAS) and the cyclic GMP-AMP receptor stimulator of interferon genes (STING), detects pathogenic DNA to trigger an innate immune reaction involving a strong type I interferon response against microbial infections[1]. The cGAS-STING pathway responds to viral, bacterial, and self-DNA. Whereas it generally mediates immune surveillance and is often neuroprotective, excessive engagement of the system can be deleterious[2]. STING-deficient mice exhibited unaltered initial development of HCC, but had higher number of large tumors at late stages of disease. In the liver of STING-deficient HCC mice, we observed reduced levels of phospho-STAT1, autophagy, and cleaved caspase3. These responses were activated in the liver by treatment with a cyclic dinucleotide (CDN) STING agonist. Importantly, CDN treatment of mice after HCC development efficiently reduced tumor size[3]. STING and IRF3 were upregulated in livers of HFD-fed mice and in FFA-induced L-O2 cells. Knocking down either STING or IRF3 led to a significant reduction in FFA-induced hepatic inflammation and apoptosis, as evidenced by modulation of the nuclear factor κB (NF-κB) signaling pathway, inflammatory cytokines, and apoptotic signaling. Additionally, STING/IRF3 knockdown enhanced glycogen storage and alleviated lipid accumulation, which were found to be associated with increased expression of hepatic enzymes in glycolysis and lipid catabolism, and attenuated expression of hepatic enzymes in gluconeogenesis and lipid synthesis. GUN35901 is a demethyl analogue of DUN99845. GUN35901 is a STING inhibitor, which inhibited the activation of the STING signal pathway and to prevent or treat a STING- mediated disease[4].
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