SN-011 is a stimulator of interferon genes (STING) antagonist.1 It binds to the STING cyclic dinucleotide binding site (Kd = 4.03 nM) and inhibits 2’3’-cGAMP-induced Ifnb expression in mouse embryonic fibroblasts (MEFs), mouse bone marrow-derived macrophages (BMDMs), and human foreskin fibroblasts (HFFs; IC50s = 127.5, 107.1, and 502.8 nM, respectively). SN-011 (1 µM) impairs recruitment of IFN regulatory factor 3 (IRF3) or TANK-binding kinase 1 (TBK1) to the STING signalosome in HEK293T cells overexpressing tagged wild-type or SAVI-linked mutant STING and IRF3 or TBK1, as well as inhibits translocation of STING from the endoplasmic reticulum (ER) to the Golgi induced by herpes simplex virus 1 (HSV-1) in HFFs. In vivo, SN-011 (5 mg/kg) increases survival and reduces Ifnb mRNA levels in the Trex1-/- mouse model of Aicardi-GoutiÈres syndrome, an autoimmune disorder characterized by constitutive activation of cGAS and IFN overproduction.
1.Hong, Z., Mei, J., Li, C., et al.STING inhibitors target the cyclic dinucleotide binding pocketProc. Natl. Acad. Sci. USA.118(24)e2105465118(2021)