CY-09
(Synonyms: 4-[[2-硫代-3-(3-三氟甲基苄基)-4-氧代噻唑烷-5-亚基]甲基]苯甲酸) 目录号 : GC19113
CY-09 是 NLRP3 炎性体的特异性抑制剂，直接靶向 NLRP3，对五种主要细胞色素 P450 酶中的每一种酶的 IC50 值为 18.9、8.18、>50、>50 和 26.0 uM。
Cas No.:1073612-91-5
Sample solution is provided at 25 µL, 10mM.
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CY-09, a specific inhibitor of the NLRP3 inflammasome, directly targets NLRP3 and has an IC50 value of 18.9, 8.18, >50, >50 and 26.0 uM for each of the five major cytochrome P450 enzymes. CY-09 directly binds to the ATP-binding motif of NLRP3 NACHT domain and inhibits NLRP3 ATPase activity, resulting in the suppression of NLRP3 inflammasome assembly and activation[1].
CY-09 exhibited a dose-dependent inhibitory effect on monosodium urate (MSU), nigericin, and ATP-induced caspase-1 activation and IL-1β secretion at the doses of 1-10 uM in LPS-primed BMDMs. Cytosolic LPS induced noncanonical NLRP3 activation in BMDMs could also be blocked by CY-09 treatment[1]. CY-09 can maintain extracellular matrix (ECM) homeostasis and regulate inflammation in TNF-α treated chondrocytes via inhibition of NLRP3 inflammasome-mediated pyroptosis[2].CY-09 reduced the production of inflammatory cytokines, intracellular Ca2+ levels, and the activation of TRPA1 by inhibiting the activation of inflammasomes, thereby reducing the proinflammatory polarization of macrophages and alleviating animal pain and injury[3]. M1-polarized macrophage infiltration and NLRP3 inflammasome activation increased in the cardiac ventricle after diabetic stroke. CY-09 restored cardiac function, The M1-polarized macrophage-NLRP3 inflammasome activation is a pathway underlying the brain-heart interaction after diabetic stroke[7].
CY-09 was tested against the five major cytochrome P450 enzymes 1A2, 2C9, 2C19, 2D6, and 3A4 with half maximal inhibitory concentration (IC50) values of 18.9, 8.18, >50, >50, and 26.0 uM, respectively, which exhibited low risk of drug drug interactions. CY-09 treatment in vivo efficiently suppressed MSU injection induced IL-1β production and neutrophil influx, suggesting that CY-09 can block MSU-induced NLRP3 inflammasome activation in vivo[1]. When investigate whether CY-09 is effective for the treatment of NAFLD in a high-fat diet (HFD)-induced mouse model.CY-09 reduces hepatic steatosis in experimental NAFLD mice and CY-09 may be a potential therapeutic drug of NAFLD in clinical practice[4]. Compared with surgery alone, sleeve gastroplasty mimicking ESG combined with CY-09 resulted in weight loss, significantly improved insulin resistance, and better remission of NAS[5]. In db/db mice, inflammation, oxidative stress, apoptosis and fibrosis increased, while CY-09 exerted renoprotection by inhibiting NLRP3 inflammasome activation[6].
References:
[1]: Jiang H, He H, et,al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med. 2017 Nov 6;214(11):3219-3238. doi: 10.1084/jem.20171419. Epub 2017 Oct 11. PMID: 29021150; PMCID: PMC5679172.
[2]: Zhang Y, Lin Z, et,al. CY-09 attenuates the progression of osteoarthritis via inhibiting NLRP3 inflammasome-mediated pyroptosis. Biochem Biophys Res Commun. 2021 May 14;553:119-125. doi: 10.1016/j.bbrc.2021.03.055. Epub 2021 Mar 22. PMID: 33765556.
[3]: Fan Y, Xue G, et,al. CY-09 Inhibits NLRP3 Inflammasome Activation to Relieve Pain via TRPA1. Comput Math Methods Med. 2021 Aug 14;2021:9806690. doi: 10.1155/2021/9806690. PMID: 34426748; PMCID: PMC8380162.
[4]: Wang X, Sun K, et,al. NLRP3 inflammasome inhibitor CY-09 reduces hepatic steatosis in experimental NAFLD mice. Biochem Biophys Res Commun. 2021 Jan 1;534:734-739. doi: 10.1016/j.bbrc.2020.11.009. Epub 2020 Nov 16. PMID: 33213837.
[5]: Sun K, Wang J, et,al. Sleeve Gastroplasty Combined with the NLRP3 Inflammasome Inhibitor CY-09 Reduces Body Weight, Improves Insulin Resistance and Alleviates Hepatic Steatosis in Mouse Model. Obes Surg. 2020 Sep;30(9):3435-3443. doi: 10.1007/s11695-020-04571-8. PMID: 32266697.
[6]: Yang M, Zhao L. The selective NLRP3-inflammasome inhibitor CY-09 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation. Curr Med Chem. 2022 Sep 22. doi: 10.2174/0929867329666220922104654. Epub ahead of print. PMID: 36154582.
[7]: Lin HB, Wei GS, et,al. Macrophage-NLRP3 Inflammasome Activation Exacerbates Cardiac Dysfunction after Ischemic Stroke in a Mouse Model of Diabetes. Neurosci Bull. 2020 Sep;36(9):1035-1045. doi: 10.1007/s12264-020-00544-0. Epub 2020 Jul 18. PMID: 32683554; PMCID: PMC7475163.
CY-09 是 NLRP3 炎性体的特异性抑制剂，直接靶向 NLRP3，对五种主要细胞色素 P450 酶中的每一种酶的 IC50 值为 18.9、8.18、>50、>50 和 26.0 uM。 CY-09 直接结合 NLRP3 NACHT 结构域的 ATP 结合基序并抑制 NLRP3 ATP 酶活性，从而抑制 NLRP3 炎性体组装和激活[1]。
CY-09 在 LPS 引发的 BMDM 中以 1-10 uM 的剂量对尿酸单钠 (MSU)、尼日利亚菌素和 ATP 诱导的 caspase-1 激活和 IL-1β 分泌表现出剂量依赖性抑制作用。 CY-09 处理也可阻断 BMDM 中胞质 LPS 诱导的非经典 NLRP3 激活[1]。 CY-09 可通过抑制 NLRP3 炎性体介导的细胞焦亡来维持细胞外基质 (ECM) 稳态并调节 TNF-α 处理的软骨细胞的炎症[2]。CY-09 减少炎症细胞因子的产生，细胞内Ca2+ 水平，以及 TRPA1 的激活，通过抑制炎性体的激活，从而减少巨噬细胞的促炎性极化，减轻动物的疼痛和损伤[3]。糖尿病卒中后心室中 M1 极化巨噬细胞浸润和 NLRP3 炎性体激活增加。 CY-09恢复心脏功能，M1极化巨噬细胞-NLRP3炎性体激活是糖尿病脑卒中后脑-心相互作用的潜在通路[7]。
CY-09 针对五种主要细胞色素 P450 酶 1A2、2C9、2C19、2D6 和 3A4 进行了测试，半数最大抑制浓度 (IC50) 值为 18.9、8.18、>50 , >50 和 26.0 uM，分别表现出药物相互作用的低风险。 CY-09 体内治疗有效抑制 MSU 注射诱导的 IL-1β 产生和中性粒细胞流入，表明 CY-09 可以阻断 MSU 诱导的体内 NLRP3 炎性体激活[1]。当研究 CY-09 在高脂饮食 (HFD) 诱导的小鼠模型中是否对治疗 NAFLD 有效时。CY-09 减少实验性 NAFLD 小鼠的肝脂肪变性，CY-09 可能是 NAFLD 的潜在治疗药物。临床实践[4].与单纯手术相比，模拟ESG的袖状胃成形术联合CY-09可减轻体重，显着改善胰岛素抵抗，更好地缓解NAS[5]。在db/db小鼠中，炎症、氧化应激、细胞凋亡和纤维化增加，而CY-09通过抑制NLRP3炎性体激活发挥肾脏保护作用[6]。
| Kinase experiment [1]: | |
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Preparation Method |
For ATPase activity assay, purified recombinant human proteins (1.4 ng/uL) were incubated at 37°C with indicated concentrations of CY-09 for 15 min in the reaction buffer. ATP (25 um, Ultra-Pure ATP) was then added, and the mixture was further incubated at 37 °C for another 40 min. |
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Reaction Conditions |
0.1-1uM CY-09 with protein incubate for 15 minutes |
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Applications |
Cy-09 inhibited the ATPase activity of purified NLRP3 at a dose of 0.1 - 1 uM. The inhibitory effect of CY-09 on NLRP3 ATPase activity was specific because it had no effect on the ATPase activity of purified NLRC4 NLRP1 NOD2 or RIG-I. |
| Cell experiment [1]: | |
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Cell lines |
MDM cells(BMDM and PMDM) |
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Preparation Method |
To induce NLRP3 inflammasome activation, MDM cells were stimulated with LPS for 3 h. CY-09 or other inhibitors were added into the culture for 30 min, and then the cells were stimulated for 4 h with MSU, Salmonella typhimurium or for 30 min with ATP or nigericin. |
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Reaction Conditions |
1-10 µM Cy-09 for 30 min |
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Applications |
Cy-09 specifically blocks NLRP3 activation in macrophages. |
| Animal experiment [1]: | |
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Animal models |
C57BL/6J mice |
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Preparation Method |
C57BL/6J mice were injected with 40 mg/kg CY-09 or vehicle 30 min before injection of MSU. After 6 h, mice were killed, and peritoneal cavities underwent lavage with 10 ml ice-cold PBS. |
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Dosage form |
40 mg/kg CY-09 (intraperitoneal injection) |
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Applications |
Cy-09 inhibited NLRP3 activation in vivo and prevented neonatal mortality in CAPS mouse model. |
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References: [1]. Jiang H, He H, et,al.Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med. 2017 Nov 6;214(11):3219-3238. doi: 10.1084/jem.20171419. Epub 2017 Oct 11. PMID: 29021150; PMCID: PMC5679172. |
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| Cas No. | 1073612-91-5 | SDF | |
| 别名 | 4-[[2-硫代-3-(3-三氟甲基苄基)-4-氧代噻唑烷-5-亚基]甲基]苯甲酸 | ||
| Canonical SMILES | OC(C1=CC=C(/C=C2SC(N(CC3=CC=CC(C(F)(F)F)=C3)C\2=O)=S)C=C1)=O | ||
| 分子式 | C19H12F3NO3S2 | 分子量 | 423.43 |
| 溶解度 | DMSO : ≥ 150 mg/mL (354.25 mM) | 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 | 2.3617 mL | 11.8083 mL | 23.6167 mL |
| 5 mM | 0.4723 mL | 2.3617 mL | 4.7233 mL |
| 10 mM | 0.2362 mL | 1.1808 mL | 2.3617 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。
Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
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