SR-717
目录号 : GC61293
SR-717 是一种非核苷酸 STING 激动剂，在 ISG-THP1 (WT) 和 ISG-THP1 cGAS KO (cGAS KO) 细胞系中的 EC50 分别为 2.1 μM 和 2.2 μM。
Cas No.:2375421-09-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
human umbilical vein endothelial cells (HUVECs) |
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Preparation Method |
The cells were exposed to 2 μM SR-717 and challenged with 10% fetal bovine serum (FBS) for 2 h. |
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Reaction Conditions |
2 μM SR-717 for two hours |
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Applications |
Pharmacological targeting of cGAS/STING-YAP signaling by both a small-molecule STING agonist, SR-717 that blocks the profibrotic activity of endothelial YAP, attenuated liver and kidney fibrosis. |
| Animal experiment [2]: | |
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Animal models |
Stinggt/gt mice |
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Preparation Method |
The tumor growth was detected by intraperitoneal injection of SR-717 (30 mg/kg, once a day, for 1 week). |
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Dosage form |
30 mg/kg SR-717 once-per-day for 1 week |
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Applications |
SR-717 (30 mg/kg intraperitoneally for 7 days) displays antitumor activity; promots the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitates antigen cross-priming |
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References: [1]. Wang L, Zhang Y, et,al. Pharmacological targeting of cGAS/STING-YAP axis suppresses pathological angiogenesis and ameliorates organ fibrosis. Eur J Pharmacol. 2022 Sep 2;932:175241. doi: 10.1016/j.ejphar.2022.175241. Epub ahead of print. PMID: 36058291. [2]. Chin EN, Yu C, et,al. Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic. Science. 2020 Aug 21;369(6506):993-999. doi: 10.1126/science.abb4255. PMID: 32820126. |
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SR-717 is a stable cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic, Antitumor activity[1]. The cGAS-STING pathway promotes the senescence of cancer cells, induces apoptosis of cancer cells, and increases the protective effect of cytotoxic T cells and natural killer cell-mediated cytotoxicity[4]. cGAS-STING pathway plays an important role in the chronic inflammatory status in various organs[5].SR-717 as a non-nucleotide STING agonist with EC50s of 2.1 μM and 2.2 μM in ISG-THP1 (WT) and ISG-THP1 cGAS KO (cGAS KO) cell lines, respectively.
Pharmacological targeting of cGAS/STING-YAP signaling by both a small-molecule STING agonist, SR-717 that blocks the profibrotic activity of endothelial YAP, attenuated liver and kidney fibrosis[2].
By STING agonist SR-717, activation of cGAS-STING pathway induced increased apoptosis, inflammation, and oxidative stress via regulating ERS and therefore resulted in pulmonary edema and pathological injury in the lungs of I/R rats[3].
References:
[1]: Chin EN, Yu C, et,al. Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic. Science. 2020 Aug 21;369(6506):993-999. doi: 10.1126/science.abb4255. PMID: 32820126.
[2]: Wang L, Zhang Y, et,al. Pharmacological targeting of cGAS/STING-YAP axis suppresses pathological angiogenesis and ameliorates organ fibrosis. Eur J Pharmacol. 2022 Sep 2;932:175241. doi: 10.1016/j.ejphar.2022.175241. Epub ahead of print. PMID: 36058291.
[3]: Huang R, Shi Q, et,al. Inhibition of the cGAS-STING Pathway Attenuates Lung Ischemia/Reperfusion Injury via Regulating Endoplasmic Reticulum Stress in Alveolar Epithelial Type II Cells of Rats. J Inflamm Res. 2022 Sep 5;15:5103-5119. doi: 10.2147/JIR.S365970. PMID: 36091334; PMCID: PMC9462969.
[4]: Du H, Xu T, et,al. cGAS-STING signaling in cancer immunity and immunotherapy. Biomed Pharmacother. 2021 Jan;133:110972. doi: 10.1016/j.biopha.2020.110972. Epub 2020 Nov 27. PMID: 33254021.
[5]: Bao T, Liu J, et,al. The cGAS-STING pathway: more than fighting against viruses and cancer. Cell Biosci. 2021 Dec 14;11(1):209. doi: 10.1186/s13578-021-00724-z. PMID: 34906241; PMCID: PMC8670263.
SR-717 是一种稳定的环磷酸鸟苷-磷酸腺苷 (cGAMP) 模拟物，具有抗肿瘤活性[1]。 cGAS-STING通路促进癌细胞衰老，诱导癌细胞凋亡，增加细胞毒性T细胞和自然杀伤细胞介导的细胞毒性的保护作用[4]。 cGAS-STING通路在多种器官的慢性炎症状态中起着重要作用[5]。SR-717作为一种非核苷酸STING激动剂，在ISG-THP1中的EC50分别为2.1 μM和2.2 μM（ WT)和ISG-THP1 cGAS KO (cGAS KO)细胞系。
小分子 STING 激动剂 SR-717 对 cGAS/STING-YAP 信号的药理学靶向作用可阻断内皮 YAP 的促纤维化活性，减轻肝肾纤维化[2]。< /p>\n
通过 STING 激动剂 SR-717，cGAS-STING 通路的激活通过调节 ERS 诱导细胞凋亡、炎症和氧化应激增加，从而导致 I/R 大鼠肺部的肺水肿和病理损伤[3 ].
| Cas No. | 2375421-09-1 | SDF | |
| Canonical SMILES | O=C(O[Li])C1=CC(F)=C(F)C=C1NC(C2=NN=C(N3C=CN=C3)C=C2)=O | ||
| 分子式 | C15H8F2LiN5O3 | 分子量 | 351.19 |
| 溶解度 | DMSO: 14.29 mg/mL (40.69 mM); Water: < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.8475 mL | 14.2373 mL | 28.4746 mL |
| 5 mM | 0.5695 mL | 2.8475 mL | 5.6949 mL |
| 10 mM | 0.2847 mL | 1.4237 mL | 2.8475 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic
Science 2020 Aug 21;369(6506):993-999.PMID:32820126DOI:10.1126/science.abb4255.
Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic that induces the same "closed" conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.
Pharmacological targeting of cGAS/STING-YAP axis suppresses pathological angiogenesis and ameliorates organ fibrosis
Eur J Pharmacol 2022 Oct 15;932:175241.PMID:36058291DOI:10.1016/j.ejphar.2022.175241.
Organ fibrosis is accompanied by pathological angiogenesis. Discovering new ways to ameliorate pathological angiogenesis may bypass organ fibrosis. The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been implicated in organ injuries and its activation inhibits endothelial proliferation. Currently, a controversy exists as to whether cGAS/STING activation exacerbates inflammation and tissue injury or mitigates damage, and whether one of these effects predominates under specific context. This study unveiled a new antifibrotic cGAS/STING signaling pathway that suppresses pathological angiogenesis in liver and kidney fibrosis. We showed that cGAS expression was induced in fibrotic liver and kidney, but suppressed in endothelial cells. cGAS genetic deletion promoted liver and kidney fibrosis and pathological angiogenesis, including occurrence of endothelial-to-mesenchymal transition. Meanwhile, cGAS deletion upregulated profibrotic Yes-associated protein (YAP) signaling in endothelial cells, which was evidenced by the attenuation of organ fibrosis in mice specifically lacking endothelial YAP. Pharmacological targeting of cGAS/STING-YAP signaling by both a small-molecule STING agonist, SR-717, and a G protein-coupled receptor (GPCR)-based antagonist that blocks the profibrotic activity of endothelial YAP, attenuated liver and kidney fibrosis. Together, our data support that activation of cGAS/STING signaling mitigates organ fibrosis and suppresses pathological angiogenesis. Further, pharmacological targeting of cGAS/STING-YAP axis exhibits the potential to alleviate liver and kidney fibrosis.
Inhibition of the cGAS-STING Pathway Attenuates Lung Ischemia/Reperfusion Injury via Regulating Endoplasmic Reticulum Stress in Alveolar Epithelial Type II Cells of Rats
J Inflamm Res 2022 Sep 5;15:5103-5119.PMID:36091334DOI:10.2147/JIR.S365970.
Purpose: Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of lung ischemia/reperfusion (I/R) injury. Cyclic GMP-AMP synthase (cGAS) is a cytosol dsDNA sensor, coupling with downstream stimulator of interferon genes (STING) located in the ER, which involves innate immune responses. The aim of our present study was to investigate the effects of cGAS on lung I/R injury via regulating ERS. Methods: We used Sprague-Dawley rats to make the lung I/R model by performing left hilum occlusion-reperfusion surgery. cGAS-specific inhibitor RU.521, STING agonist SR-717, and 4-phenylbutyric acid (4-PBA), the ERS inhibitor, were intraperitoneally administered in rats. Double immunofluorescent staining was applied to detect the colocalization of cGAS or BiP, an ERS protein, with alveolar epithelial type II cells (AECIIs) marker. We used transmission electron microscopy to examine the ultrastructure of ER and mitochondria. Apoptosis and oxidative stress in the lungs were assessed, respectively. The profiles of pulmonary edema and lung tissue injury were evaluated. And the pulmonary ventilation function was measured using a spirometer system. Results: In lung I/R rats, the cGAS-STING pathway was upregulated, which implied they were activated. After cGAS-STING pathway was inhibited or activated in lung I/R rats, the ERS was alleviated after cGAS was inhibited, while when STING was activated after lung I/R, ERS was aggravated in the AECIIs, these results suggested that cGAS-STING pathway might trigger ERS responses. Furthermore, activation of cGAS-STING pathway induced increased apoptosis, inflammation, and oxidative stress via regulating ERS and therefore resulted in pulmonary edema and pathological injury in the lungs of I/R rats. Inhibition of cGAS-STING pathway attenuated ERS, therefore attenuated lung injury and promoted pulmonary ventilation function in I/R rats. Conclusion: Inhibition of the cGAS-STING pathway attenuates lung ischemia/reperfusion injury via alleviating endoplasmic reticulum stress in alveolar epithelial type II cells of rats.
Design, Synthesis, and Biological Evaluation of Bipyridazine Derivatives as Stimulator of Interferon Genes (STING) Receptor Agonists
J Med Chem 2023 Mar 9;66(5):3327-3347.PMID:36808996DOI:10.1021/acs.jmedchem.2c01714.
The development of stimulator of interferon genes (STING) agonists has been of potential applications for the treatment of cancer and infectious diseases. Based on the crystal structure of SR-717 bound to hSTING, we designed and synthesized a novel series of bipyridazine derivatives as highly potent STING agonists. Among them, compound 12L led to significant thermal stability shifts of the common alleles of hSTING, as well as that of mSTING. 12L also displayed potent activities in various hSTING alleles and mSTING competition binding assay. Specifically, 12L displayed higher cell-based activities than SR-717 in both human THP1 (EC50 = 0.38 ± 0.03 μM) and mouse RAW 264.7 cells (EC50 = 12.94 ± 1.78 μM), and was validated to activate the downstream signaling pathway of STING via a STING-dependent manner. Furthermore, compound 12L showed favorable pharmacokinetic (PK) properties and antitumor efficacy. These findings suggested that compound 12L has development potential as an antitumor agent.