H-151
目录号 : GC34610
H-151是STING的低分子量拮抗剂,可阻断激活诱导的STING棕榈酰化,对STING信号传导有显著抑制作用,可用于自身炎症性疾病的研究。
Cas No.:941987-60-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
THP-1 cells |
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Preparation Method |
Cells were pretreated with H-151 (1 µM) for 6 h, followed by stimulating with 2 ,3 -cGAMP (cGAMP, 10 µg/ml) for 12 h |
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Reaction Conditions |
1 µM; 6 h |
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Applications |
H-151 inhibited the induction of IFN-β mRNA expression triggered by cGAMP in THP-1 cells. |
| Animal experiment [2]: | |
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Animal models |
Female BALB/c mice (model of psoriasis induced by imiquimod) |
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Preparation Method |
Mice were randomly divided into four groups (n = 8): control, model, model with 250 mg/kg H-151 (2.5% H-151 cream) and model with 500 mg/kg H-151 (5% H-151 cream) groups. A topical dose of 62.5 mg of 5% imiquimod cream was applied, once daily, to the shaved back and right ear in a ratio of 4:1 for five consecutive days to induce psoriasis-like skin inflammation. Control group was only treated with control cream (a mixture of wood fat and Vaseline in the ratio of one to one) on the shaved back and right ear in a ratio of 4:1 twice daily, 0.2 g per mice per treatment. The model group was treated with the control cream and imiquimod cream on the shaved back and right ear in a ratio of 4:1. Treatment groups were treated with H-151 creams (2.5% or 5% H-151 creams containing the same components as control cream) and imiquimod cream on the shaved back and right ear in a ratio of 4:1. Before imiquimod administration, the shaved back and right ear were topically treated with control cream or H-151 creams (250 or 500 mg/kg) in a ratio of 4:1, 0.2 g per mice. After imiquimod administration, another treatment with control cream or H-151 creams (250 or 500 mg/kg) was applied in the same manner mentioned above. The interval between all the treatments was 4 h. The body weight was measured every day. |
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Dosage form |
250 /500 mg/kg; on the shaved back and right ear;5days |
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Applications |
H-151 ameliorates IMQ(imiquimod)-induced psoriasis-like dermatitis. |
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References: [1]. Pan Y, You Y, et,al. The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation. Br J Pharmacol. 2021 Dec;178(24):4907-4922. doi: 10.1111/bph.15673. Epub 2021 Oct 30. PMID: 34460100. |
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H-151 is a low MW antagonist of STING, which blocks the activation-induced palmitoylation of STING, and exhibits significant inhibitory effects on STING signalling H-151 can be used in the study of autoinflammatory diseases[1-2].
H-151(1 µM; 6 h) exerts anti-psoriasis effect through inhibiting STING/NF-κB signalling[3]. H-151(2.5 µM; 24h) improved the inflammation of peripheral blood mononuclear cells and Coatomer complex I (COPI)-deficient cell lines in patients with COPA syndrome[4].
H-151(250 /500 mg/kg; on the shaved back and right ear;5days) displayed anti-inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo[3]. H-151 downregulated the expression of granzymes and the pro-inflammatory cytokines IL-1β, IL-6, IL-15, IL-23A, and IFN-γ, and induced a pro-resolution macrophage phenotypes in ALS patients [5]. Administration of H-151 alleviated pulmonary edema, hemorrhage, thickening of the alveolar septum and infiltration of inflammatory cells; DNA damage in pulmonary tissue; and disruption of intercellular junctions in LPS-induced ALI [6]. H-151(750 nmol; i.p) treatment preserves myocardial function 28 days after myocardial infarction (MI)[7].
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]. Li J, Lu Y, et,al. Blocking cGAS/STING signaling protects against sepsis-associated acute liver injury. Int Immunopharmacol. 2022 Dec;113(Pt A):109276. doi: 10.1016/j.intimp.2022.109276. Epub 2022 Oct 15. PMID: 36252490.
[3]. Pan Y, You Y, et,al. The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation. Br J Pharmacol. 2021 Dec;178(24):4907-4922. doi: 10.1111/bph.15673. Epub 2021 Oct 30. PMID: 34460100.
[4]. Steiner A, Hrovat-Schaale K, et,al. Deficiency in coatomer complex I causes aberrant activation of STING signalling. Nat Commun. 2022 Apr 28;13(1):2321. doi: 10.1038/s41467-022-29946-6. PMID: 35484149; PMCID: PMC9051092.
[5]. Zamiri K, Kesari S, et,al. Therapy of autoimmune inflammation in sporadic amyotrophic lateral sclerosis: Dimethyl fumarate and H-151 downregulate inflammatory cytokines in the cGAS-STING pathway. FASEB J. 2023 Aug;37(8):e23068. doi: 10.1096/fj.202300573R. PMID: 37436778; PMCID: PMC10619685.
[6]. Zhao J, Zhen N, et,al. NETs Promote Inflammatory Injury by Activating cGAS-STING Pathway in Acute Lung Injury. Int J Mol Sci. 2023 Mar 7;24(6):5125. doi: 10.3390/ijms24065125. PMID: 36982193; PMCID: PMC10049640.
[7]. Hu S, Gao Y, et,al. The selective STING inhibitor H-151 preserves myocardial function and ameliorates cardiac fibrosis in murine myocardial infarction. Int Immunopharmacol. 2022 Jun;107:108658. doi: 10.1016/j.intimp.2022.108658. Epub 2022 Mar 9. PMID: 35278833.
H-151是STING的低分子量拮抗剂,可阻断激活诱导的STING棕榈酰化,对STING信号传导有显著抑制作用,可用于自身炎症性疾病的研究[1-2]。
H-151(1µM;6 h)通过抑制STING/NF-κB信号通路发挥抗银屑病作用[3]。H-151(2.5µM;24h)改善了COPA综合征患者外周血单核细胞和Coatomer complex I (COPI)缺陷细胞系的炎症反应[4]。
H-151(250 /500 mg/kg; on the shaved back and right ear;5days)在角质形成细胞和免疫细胞中均表现出抗炎活性,并在体内降低银屑病反应的严重程度[3]。H-151下调颗粒酶和促炎细胞因子IL-1β、IL-6、IL-15、IL-23A和IFN-γ的表达,诱导ALS患者巨噬细胞出现促溶解表型[5]。H-151可减轻肺水肿、出血、肺泡隔增厚及炎症细胞浸润;肺组织DNA损伤;以及LPS诱导ALI中细胞间连接的破坏[6]。H-151(750 nmol; i.p)治疗可在心肌梗死后28天保持心肌功能[7]。
| Cas No. | 941987-60-6 | SDF | |
| Canonical SMILES | O=C(NC1=CNC2=C1C=CC=C2)NC3=CC=C(CC)C=C3 | ||
| 分子式 | C17H17N3O | 分子量 | 279.34 |
| 溶解度 | DMSO : 125 mg/mL (447.48 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.5799 mL | 17.8993 mL | 35.7987 mL |
| 5 mM | 0.716 mL | 3.5799 mL | 7.1597 mL |
| 10 mM | 0.358 mL | 1.7899 mL | 3.5799 mL |
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The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation
Br J Pharmacol 2021 Dec;178(24):4907-4922.PMID:34460100DOI:10.1111/bph.15673.
Background and purpose: Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA-driven immune responses. In vitro and in vivo anti-psoriasis effects of STING antagonist H-151 were explored. Experimental approach: We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H-151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H-151 on imiquimod-induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed. Key results: Gene expressions of STING and its downstream target were up-regulated in lesional skin samples from psoriasis patients. Topical administration of H-151 attenuated the skin lesions in imiquimod-induced psoriatic mouse model, while the secretion of pro-inflammatory cytokines (IL-17, IL-23 and IL-6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H-151 treatment. Mechanistically, H-151 inhibited STING/NF-κB signalling in both keratinocytes and immune cells. Conclusion and implications: H-151 displayed anti-inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications.
The selective STING inhibitor H-151 preserves myocardial function and ameliorates cardiac fibrosis in murine myocardial infarction
Int Immunopharmacol 2022 Jun;107:108658.PMID:35278833DOI:10.1016/j.intimp.2022.108658.
Background: During myocardial infarction (MI), the stimulation of the cGAS-STING-IRF3 pathway in infiltrated macrophages can induce the apoptosis of cardiomyocytes and the fibrosis of cardiac fibroblasts, while H-151 is reported as a selective STING inhibitor. We intended to use H-151 to alleviate MI injury. Methods: Male C57BL/6J mice were subjected to induce MI, while H-151 (750 nmol) were used for treatment. Myocardial function was assessed through echocardiology and cardiac fibrosis was evaluated by Masson's Trichrome-staining. The stimulation of the STING pathway and the aggravation of inflammation was assessed by levels of protein and mRNA. BMDMs were stimulated by dsDNA extracted from the murine heart, while H-151 was used as treatment. After co-culturing adult cardiomyocytes and cardiac fibroblasts with supernatant of BMDMs, the apoptosis of adult cardiomyocytes and the fibrosis of cardiac fibroblasts was assessed. Results: H-151 treatment showed significant function in preserving myocardial function and decreasing cardiac fibrosis 28 days after MI. H-151 treatment showed significant function in inhibiting the cGAS-STING-IRF3 pathway and inflammation, especially type I interferon response. H-151 could alleviate the type I interferon response in BMDMs elicited by cardiac dsDNA, and thus H-151 could attenuate the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts after co-culturing them with the supernatant of BMDMs. Conclusions: H-151, a selective inhibitor of the cGAS-STING-IRF3 pathway, can preserve myocardial function and alleviate cardiac fibrosis after MI by inhibiting the type I interferon response in infiltrated macrophages triggered by cardiac dsDNA which increase the apoptosis of adult cardiomyocytes and fibrosis of cardiac fibroblasts.
Deficiency in coatomer complex I causes aberrant activation of STING signalling
Nat Commun 2022 Apr 28;13(1):2321.PMID:35484149DOI:10.1038/s41467-022-29946-6.
Coatomer complex I (COPI) mediates retrograde vesicular trafficking from Golgi to the endoplasmic reticulum (ER) and within Golgi compartments. Deficiency in subunit alpha causes COPA syndrome and is associated with type I IFN signalling, although the upstream innate immune sensor involved was unknown. Using in vitro models we find aberrant activation of the STING pathway due to deficient retrograde but probably not intra-Golgi transport. Further we find the upstream cytosolic DNA sensor cGAS as essentially required to drive type I IFN signalling. Genetic deletion of COPI subunits COPG1 or COPD similarly induces type I IFN activation in vitro, which suggests that inflammatory diseases associated with mutations in other COPI subunit genes may exist. Finally, we demonstrate that inflammation in COPA syndrome patient peripheral blood mononuclear cells and COPI-deficient cell lines is ameliorated by treatment with the small molecule STING inhibitor H-151, suggesting targeted inhibition of the cGAS/STING pathway as a promising therapeutic approach.
STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion
Acta Pharmacol Sin 2022 Aug;43(8):2055-2066.PMID:PMC9343420DOI:10.1038/s41401-021-00813-2.
Acute lung injury (ALI) is a common and devastating clinical disorder featured by excessive inflammatory responses. Stimulator of interferon genes (STING) is an indispensable molecule for regulating inflammation and immune response in multiple diseases, but the role of STING in the ALI pathogenesis is not well elucidated. In this study, we explored the molecular mechanisms of STING in regulating lipopolysaccharide (LPS)-induced lung injury. Mice were pretreated with a STING inhibitor C-176 (15, 30 mg/kg, i.p.) before LPS inhalation to induce ALI. We showed that LPS inhalation significantly increased STING expression in the lung tissues, whereas C-176 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. Consistently, in vitro experiments conducted in TNF-α-stimulated HMEC-1cells (common and classic vascular endothelial cells) revealed that human STING inhibitor H-151 or STING siRNA downregulated the expression levels of adhesion molecule and chemokines in HMEC-1cells, accompanied by decreased adhesive ability and chemotaxis of immunocytes upon TNF-α stimulation. We further revealed that STING inhibitor H-151 or STING knockdown significantly decreased the phosphorylation of transcription factor STAT1, which subsequently influenced its binding to chemokine CCL2 and adhesive molecule VCAM-1 gene promoter. Collectively, STING inhibitor can alleviate LPS-induced ALI in mice by preventing vascular endothelial cells-mediated immune cell chemotaxis and adhesion, suggesting that STING may be a promising therapeutic target for the treatment of ALI.
STING inhibition accelerates the bone healing process while enhancing type H vessel formation
FASEB J 2021 Nov;35(11):e21964.PMID:34694030DOI:10.1096/fj.202100069RR.
The stimulator of interferon genes (STING), one of the critical factors of innate immunity, is indicated to be closely related to angiogenesis. This study examined STING's role in angiogenesis and the formation of type H vessels, a specific subtype of bone vessels that regulates bone healing. Different concentrations of 2',3'-cGAMP, and H-151 or C-176 were applied to activate or inhibit STING, respectively. Human umbilical vein endothelial cells were used to examine the effect of STING on angiogenesis in vitro; cell viability, cell migration, and quantitative real-time polymerase chain reactions were performed. Also, the metatarsal experiment was applied as ex vivo proof. Bone fracture or defect mice models were used to examine the effect of STING in vivo; the bone healing process was evaluated by radiography weekly and by μCT on the 14th day after surgery. The formation of type H vessels (CD31hi Emcnhi endothelial cells) and osteogenesis (OCN-positive cells) was assessed using the cryosection and paraffin section. STING activation inhibited angiogenesis both in vitro and ex vivo and slowed down the bone healing process in vivo. Histological analysis showed an increased callus formation, fewer type H vessels, and almost no callus mineralization in the STING activation group compared to the control group. By contrast, H-151 (a hsSTING inhibitor) promoted angiogenesis at a low dose. Moreover, inhibition of mmSTING by C-176 enhanced type H vessels' formation, implying osteogenesis promotion in bone healing (higher bone volume density and more OCN-positive cells). Our data suggested that STING inhibition accelerates the bone healing process while enhancing type H vessel formation.