C-176 (STING inhibitor 1)

C-176 (STING inhibitor 1) strongly reduces STING-mediated, but not RIG-I- or TBK1-mediated, IFNβ reporter activity. It directly targets mouse STING (mmSTING) but not human STING (hsSTING)^[1].

Cytotoxicity against human HCC1806 cells assessed as reduction in cell viability incubated for 3 days by cell-titer-Glo reagent based assay, IC50 = 6.2 μM. C-176 (STING inhibitor 1) induced apoptosis in HCC-1806 cells, C-176 (STING inhibitor 1) induced CHOP expression in HCC-1806 cells^[2].STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 (STING inhibitor 1) substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 (STING inhibitor 1) significantly alleviated both short-term and persistent neurological dysfunction after SAH^[3].Inhibition of mmSTING by C-176 (STING inhibitor 1) enhanced type H vessels' formation, implying osteogenesis promotion in bone healing (higher bone volume density and more OCN-positive cells). STING inhibition accelerates the bone healing process while enhancing type H vessel formation^[7].

C-176 (STING inhibitor 1) covalently binds to Cys91 of STING preventing activation via blockade of palmitoylation at Cys91. Treatment of Trex-/- mice with C-176 (STING inhibitor 1) resulted in a significant reduction in serum levels of Type I Interferons and amelioration of systemic inflammation^[1]. When explored the molecular mechanisms of STING in regulating lipopolysaccharide (LPS)-induced lung injury. Mice were pretreated with a STING inhibitor C-176 (STING inhibitor 1) (15, 30 mg/kg) before LPS inhalation to induce ALI. LPS inhalation significantly increased STING expression in the lung tissues, whereas C-176 (STING inhibitor 1) pretreatment dose-dependently suppressed the expression of STING, decreased the production of inflammatory cytokines including TNF-α, IL-6, IL-12, and IL-1β, and restrained the expression of chemokines and adhesion molecule vascular cell adhesion protein-1 (VCAM-1) in the lung tissues^[4].Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta. Pharmacological blockade of STING using a specific inhibitor, C-176 (STING inhibitor 1), ameliorated atherogenesis in Apoe-/- mice^[5]. Treatment with the STING inhibitor, C-176, suppressed EBV-induced transformation in peripheral blood mononuclear cells. In an EBV-LPD mouse model, C-176 (STING inhibitor 1) treatment also inhibited tumor formation and prolonged survival^[6].

References:
[1]: Haag SM, Gulen MF, et,al. Targeting STING with covalent small-molecule inhibitors. Nature. 2018 Jul;559(7713):269-273. doi: 10.1038/s41586-018-0287-8. Epub 2018 Jul 4. PMID: 29973723.
[2]: Duan H, Li Y, et,al. Identification of 5-nitrofuran-2-amide derivatives that induce apoptosis in triple negative breast cancer cells by activating C/EBP-homologous protein expression. Bioorg Med Chem. 2015 Aug 1;23(15):4514-4521. doi: 10.1016/j.bmc.2015.06.011. Epub 2015 Jun 14. PMID: 26116180; PMCID: PMC5567983.
[3]: Peng Y, Zhuang J, et,al. Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage. J Neuroinflammation. 2020 May 25;17(1):165. doi: 10.1186/s12974-020-01830-4. PMID: 32450897; PMCID: PMC7247752.
[4]: Li Y, Su J, et,al. Targeted next-generation sequencing of deaf patients from Southwestern China. Mol Genet Genomic Med. 2021 Apr;9(4):e1660. doi: 10.1002/mgg3.1660. Epub 2021 Mar 16. PMID: 33724713; PMCID: PMC8123756.
[5]: Pham PT, Fukuda D, et,al. STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases. Eur Heart J. 2021 Nov 7;42(42):4336-4348. doi: 10.1093/eurheartj/ehab249. PMID: 34226923.
[6]: Miyagi S, Watanabe T, et,al. A STING inhibitor suppresses EBV-induced B cell transformation and lymphomagenesis. Cancer Sci. 2021 Dec;112(12):5088-5099. doi: 10.1111/cas.15152. Epub 2021 Oct 11. PMID: 34609775; PMCID: PMC8645724.
[7]: Chen X, He W, et,al. STING inhibition accelerates the bone healing process while enhancing type H vessel formation. FASEB J. 2021 Nov;35(11):e21964. doi: 10.1096/fj.202100069RR. PMID: 34694030.

C-176（STING 抑制剂 1）强烈降低 STING 介导的,但不降低 RIG-I 或 TBK1 介导的 IFNβ 报告基因活性。它直接针对小鼠 STING (mmSTING) 而不是人类 STING (hsSTING)^[1]。

对人 HCC1806 细胞的细胞毒性通过基于细胞滴度-Glo 试剂的测定评估为细胞活力降低 3 天,IC50 = 6.2 μM。 C-176（STING抑制剂1）诱导HCC-1806细胞凋亡,C-176（STING抑制剂1）诱导HCC-1806细胞表达CHOP^[2]。STING主要分布于小胶质细胞, SAH 后小胶质细胞 STING 表达显着增加。 C-176（STING 抑制剂 1）的给药显着减轻了 SAH 引起的脑水肿和神经元损伤。更重要的是,C-176（STING 抑制剂 1）显着缓解 SAH 后的短期和持续性神经功能障碍^[3]。C-176（STING 抑制剂 1）增强 H 型血管对 mmSTING 的抑制作用' 形成,意味着骨愈合中的成骨促进（更高的骨体积密度和更多的 OCN 阳性细胞）。抑制 STING 可加速骨愈合过程,同时促进 H 型血管形成^[7]。

C-176（STING 抑制剂 1）共价结合 STING 的 Cys91,通过阻断 Cys91 处的棕榈酰化来防止激活。用 C-176（STING 抑制剂 1）处理 Trex-/- 小鼠可显着降低血清 I 型干扰素水平并改善全身炎症^[1]。当探索 STING 调节脂多糖 (LPS) 诱导的肺损伤的分子机制时。在吸入 LPS 以诱导 ALI 之前,用 STING 抑制剂 C-176（STING 抑制剂 1）（15、30 mg/kg）预处理小鼠。 LPS 吸入显着增加肺组织中的 STING 表达,而 C-176（STING 抑制剂 1）预处理剂量依赖性地抑制 STING 的表达,减少炎症细胞因子的产生,包括 TNF-α、IL-6、IL-12 和IL-1β,抑制肺组织中趋化因子和粘附分子血管细胞粘附蛋白-1（VCAM-1）的表达^[4]。Apoe-/-小鼠Sting基因缺失减少主动脉弓的动脉粥样硬化病变、斑块中的脂质和巨噬细胞聚集以及主动脉中炎症分子的表达。使用特异性抑制剂 C-176（STING 抑制剂 1）对 STING 进行药理学阻断,可改善 Apoe-/- 小鼠的动脉粥样硬化形成^[5]。用 STING 抑制剂 C-176 治疗可抑制 EBV 诱导的外周血单核细胞转化。在 EBV-LPD 小鼠模型中,C-176（STING 抑制剂 1）治疗还可抑制肿瘤形成并延长生存期^[6]。