MCC950 sodium
(Synonyms: N-[[(1,2,3,5,6,7-六氢-S-引达省-4-基)氨基]羰基]-4-(1-羟基-1-甲基乙基)-2-呋喃磺酰胺单钠盐,CRID3 sodium salt ) 目录号 : GC10634
An inhibitor of NLRP3 inflammasome activation
Cas No.:256373-96-3
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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- Purity: >98.00%
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- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Bone marrow, HEK293T cells |
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Preparation Method |
MCC950 sodium salt is highly soluble in aqueous solutions |
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Reaction Conditions |
0.001–10 µM, 30 min |
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Applications |
The half-maximal inhibitory concentration (IC50) of MCC950 in BMDM was approximately 7.5 nM, while in HMDM it had a similar inhibitory capacity (IC50 = 8.1 nM). |
| Animal experiment [2]: | |
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Animal models |
C57BL/6 mice |
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Preparation Method |
MCC950 sodium salt is highly soluble in aqueous solutions. |
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Dosage form |
50 mg/kg, Intraperitoneal injection |
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Applications |
MCC950 not only inhibits NLRP3 in vivo and attenuates EAE severity, but also rescues a mouse model of CAPS and inhibits NLRP3 in human MWS cells. |
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References: [1]. Coll, Rebecca C et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature medicine vol. 21,3 (2015): 248-55. [2]. Zhai, Yadong et al. Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice. Molecules (Basel, Switzerland) vol. 23,3 522. 27 Feb. 2018. |
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MCC950 is a potent, selective, small molecule inhibitor of NLRP3. MCC950 blocks canonical and non-canonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibits NLRP3 but not AIM2, NLRC4 or NLRP1 activation. MCC950 reduces Interleukin-1p (IL-1β) production in vivo and attenuates the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescues neonatal lethality in a mouse model of CAPS and is active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for the further study of the NLRP3 inflammasome in human health and disease.[1]
The half-maximal inhibitory concentration (IC50) of MCC950 in BMDM was approximately 7.5 nM, while in HMDM it had a similar inhibitory capacity (IC50 = 8.1 nM). Cells were first primed with LPS then pre-treated with MCC950 and lastly stimulated with the NLRP3 stimulus ATP. Treating cells with nanomolar concentrations of MCC950 dose dependently inhibited the release of IL-1β in BMDM, HMDM and PBMC. [1]
Mice were pre-treated with MCC950 one hour before i.p. injection of LPS and were assessed two hours later. Pre-treatment with MCC950 reduced serum concentrations of IL-1β and IL-6 while it did not considerably decrease the amount of TNF-α, indicating that MCC950 is active in vivo.Besides, treatment of db/db mice with NLRP3 inflammasome inhibitor MCC950 ameliorated anxiety- and depression-like behaviors as well as cognitive dysfunction, and reversed increased NLRP3, ASC, and IL-1βexpression levels and caspase-1 activity in hippocampus. Moreover, MCC950 treatment significantly improved insulin sensitivity in db/db mice.[1,2]
References:
[1]. Coll, Rebecca C et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature medicine vol. 21,3 (2015): 248-55.
[2]. Zhai, Yadong et al. Inhibiting the NLRP3 Inflammasome Activation with MCC950 Ameliorates Diabetic Encephalopathy in db/db Mice. Molecules (Basel, Switzerland) vol. 23,3 522. 27 Feb. 2018.
MCC950 是一种有效的选择性小分子 NLRP3 抑制剂。 MCC950 在纳摩尔浓度下阻断经典和非经典 NLRP3 激活。 MCC950 特异性抑制 NLRP3，但不抑制 AIM2、NLRC4 或 NLRP1 激活。 MCC950 减少体内白细胞介素-1p (IL-1β) 的产生并减轻实验性自身免疫性脑脊髓炎 (EAE) 的严重程度，EAE 是一种多发性硬化症的疾病模型。此外，MCC950 治疗可挽救 CAPS 小鼠模型中的新生儿致死率，并且在 Muckle-Wells 综合征患者的离体样本中具有活性。因此，MCC950 是一种潜在的治疗 NLRP3 相关综合征（包括自身炎症和自身免疫性疾病）的药物，也是进一步研究 NLRP3 炎性体在人类健康和疾病中的作用的工具。[1]
MCC950 在 BMDM 中的半数最大抑制浓度 (IC50) 约为 7.5 nM，而在 HMDM 中具有相似的抑制能力 (IC50 = 8.1纳米）。细胞首先用 LPS 引发，然后用 MCC950 预处理，最后用 NLRP3 刺激物 ATP 刺激。用纳摩尔浓度的 MCC950 处理细胞会剂量依赖性地抑制 BMDM、HMDM 和 PBMC 中 IL-1β 的释放。 [1]
小鼠在腹腔注射前一小时用 MCC950 进行预处理。注射 LPS 并在两小时后进行评估。用 MCC950 预处理降低了 IL-1β 和 IL-6 的血清浓度，同时没有显着降低 TNF-α 的量，表明 MCC950 在体内具有活性。此外，用 NLRP3 炎性体抑制剂 MCC950 治疗 db/db 小鼠改善了焦虑和抑郁样行为以及认知功能障碍，并逆转了海马中增加的 NLRP3、ASC 和 IL-1β 表达水平和 caspase-1 活性。此外，MCC950 治疗显着改善了 db/db 小鼠的胰岛素敏感性。[1,2]
| Cas No. | 256373-96-3 | SDF | |
| 别名 | N-[[(1,2,3,5,6,7-六氢-S-引达省-4-基)氨基]羰基]-4-(1-羟基-1-甲基乙基)-2-呋喃磺酰胺单钠盐,CRID3 sodium salt | ||
| 化学名 | sodium ((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((4-(2-hydroxypropan-2-yl)furan-2-yl)sulfonyl)amide | ||
| Canonical SMILES | O=C(NC1=C2CCCC2=CC3=C1CCC3)[N-]S(=O)(C4=CC(C(O)(C)C)=CO4)=O.[Na+] | ||
| 分子式 | C20H23N2NaO5S | 分子量 | 426.5 |
| 溶解度 | ≥ 21.45 mg/mL in DMSO, ≥ 100 mg/mL in Water with gentle warming, ≥ 43 mg/mL in EtOH | 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 | 2.3447 mL | 11.7233 mL | 23.4467 mL |
| 5 mM | 0.4689 mL | 2.3447 mL | 4.6893 mL |
| 10 mM | 0.2345 mL | 1.1723 mL | 2.3447 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。
Target of MCC950 in Inhibition of NLRP3 Inflammasome Activation: a Literature Review
Inflammation2020 Feb;43(1):17-23.PMID: 31646445DOI: 10.1007/s10753-019-01098-8
MCC950 has been proposed as a specific small molecule inhibitor that can selectively block NLRP3 inflammasome activation. However, the exact mechanism of its action is still ambiguous. Accumulating investigations imply that chloride efflux-dependent ASC speck oligomerization and potassium efflux-dependent activation of caspase-1 are the two relatively independent, but indispensable events for NLRP3 inflammasome activation. Previous studies suggested that influence of MCC950 on potassium efflux and its consequent events such as interaction between NEK7 and NLRP3 are limited. However, inhibiting chloride intracellular channel-dependent chloride efflux leads to a modification of inflammatory response, which is similar to the function of MCC950. Based on these findings, we shed new insights on the understanding of MCC950 that its function might correlate with chloride efflux, chloride intracellular channels, or other targets that act upstream of chloride efflux.
NLRP3 inflammasome inhibition with MCC950 improves diabetes-mediated cognitive impairment and vasoneuronal remodeling after ischemia
Pharmacol Res2019 Apr;142:237-250.PMID: 30818045DOI: 10.1016/j.phrs.2019.01.035
Diabetes increases the risk and worsens the progression of cognitive impairment via the greater occurrence of small vessel disease and stroke. Yet, the underlying mechanisms are not fully understood. It is now accepted that cardiovascular health is critical for brain health and any neurorestorative approaches to prevent/delay cognitive deficits should target the conceptual neurovascular unit (NVU) rather than neurons alone. We have recently shown that there is augmented hippocampal NVU remodeling after a remote ischemic injury in diabetes. NLRP3 inflammasome signaling has been implicated in the development of diabetes and neurodegenerative diseases, but little is known about the impact of NLRP3 activation on functional and structural interaction within the NVU of hippocampus, a critical part of the brain that is involved in forming, organizing, and storing memories. Endothelial cells are at the center of the NVU and produce trophic factors such as brain derived neurotrophic factor (BDNF) contributing to neuronal survival, known as vasotrophic coupling. Therefore, the aims of this study focused on two hypotheses: 1) diabetes negatively impacts hippocampal NVU remodeling and worsens cognitive outcome after stroke, and 2) NLRP3 inhibition with MCC950 will improve NVU remodeling and cognitive outcome following stroke via vasotrophic (un)coupling between endothelial cells and hippocampal neurons. Stroke was induced through a 90-min transient middle cerebral artery occlusion (MCAO) in control and high-fat diet/streptozotocin-induced (HFD/STZ) diabetic male Wistar rats. Saline or MCC950 (3 mg/kg), an inhibitor of NLRP3, was injected at 1 and 3 h after reperfusion. Cognition was assessed over time and neuronal density, blood-brain barrier (BBB) permeability as well as NVU remodeling (aquaporin-4 [AQP4] polarity) was measured on day 14 after stroke. BDNF was measured in endothelial and hippocampal neuronal cultures under hypoxic and diabetes-mimicking condition with and without NLRP3 inhibition. Diabetes increased neuronal degeneration and BBB permeability, disrupted AQP4 polarity, impaired cognitive function and amplified NLRP3 activation after ischemia. Inhibition with MCC950 improved cognitive function and vascular integrity after stroke in diabetic animals and prevented hypoxia-mediated decrease in BDNF secretion. These results are the first to provide essential data showing MCC950 has the potential to become a therapeutic to prevent neurovascular remodeling and worsened cognitive decline in diabetic patients following stroke.
MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition
Nat Chem Biol2019 Jun;15(6):556-559.PMID: 31086327DOI: 10.1038/s41589-019-0277-7
Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and specific small-molecule inhibitor of the NLRP3 pathway, but its molecular target is not defined. Here, we show that MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, thereby blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation.
MCC950 closes the active conformation of NLRP3 to an inactive state
Nat Chem Biol2019 Jun;15(6):560-564.PMID: 31086329DOI: 10.1038/s41589-019-0278-6
NLRP3 (NOD-like receptor pyrin domain-containing protein 3) is an innate immune sensor that contributes to the development of different diseases, including monogenic autoinflammatory syndromes, gout, atherosclerosis, and Alzheimer's disease. The molecule sulfonylurea MCC950 is a NLRP3 inflammasome inhibitor with potential clinical utility. However, the mechanism of action of MCC950 remains unknown. Here, we characterize the mechanism of action of MCC950 in both wild-type and autoinflammatory-related NLRP3 mutants, and demonstrate that MCC950 closes the 'open' conformation of active NLRP3.
Protection of Mcc950 against high-glucose-induced human retinal endothelial cell dysfunction
Cell Death Dis2017 Jul 20;8(7):e2941.PMID: 28726778DOI: 10.1038/cddis.2017.308
Diabetic retinopathy (DR) is a well-known microvascular complication related to inflammation. Mcc950 is a potent and specific inhibitor of the NLRP3 inflammasome but its influence on DR has not been studied. Thus, we evaluated the anti-inflammatory effects of Mcc950 on high-glucose-induced human retinal endothelial cells (HRECs) and the potential underlying mechanism. In surgical excised proliferative membranes from DR patients, high expression of NLRP3, caspase 1 and IL-1β was observed and co-localization of NLRP3 and IL-1β occurred in CD31+ labeled HRECs. Moreover, in high-glucose-stimulated HRECs, increased production of the NLRP3 inflammasome activation and severe apoptosis were rescued with Mcc950 treatment. Additionally, the inhibitory effect of Mcc950 was mimicked through downregulation of NEK7 by siRNA in high-glucose-induced HRECs and Mcc950 treatment remarkably inhibited Nek7 and NLRP3 interactions by co-immunoprecipitation, suggesting that Mcc950 may be a potentially protective agent against inflammation, likely via downregulation of the Nek7-NLRP3 pathway. In conclusion, Mcc950 inhibited HREC dysfunction under high-glucose conditions and this research may offer insight for future pharmaceutical approaches for treating DR.