MCC950 (CP-456773)
(Synonyms: CP-456773; CRID3) 目录号 : GC31644
An inhibitor of NLRP3 inflammasome activation
Cas No.:210826-40-7
Sample solution is provided at 25 µL, 10mM.
- Vet Res 53.1 (2022)：10.PMID:35123552
- Behav Brain Res 428 (2022)：113879.PMID:35390431
- Immun Inflamm Dis 12.12 (2024)：e70094.PMID:39679857
- Phytomedicine 94 (2022)：153849.PMID:34775360
- Chem-Biol Interact 368 (2022)：110229.PMID:36354081
- Immun Inflamm Dis 12.1 (2024)：e1145.
- Neuropsych Dis Treat (2024)：2335-2346.
MCC950 is a potent and selective NLRP3 inhibitor with IC50s of 7.5 and 8.1 nM in BMDMs and HMDMs, respectively.
MCC950 blocks canonical and non-canonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibits NLRP3 but not AIM2, NLRC4 or NLRP1 activation. The effect of MCC950 on NLRP3 inflammasome activation is tested in mouse bone marrow derived macrophages (BMDM) and human monocyte derived macrophages (HMDM). The IC50 of MCC950 in BMDM is approximately 7.5 nM, while in HMDM it has a similar inhibitory capacity (IC50=8.1 nM). MCC950 also dose dependently inhibit IL-1β but not TNF-α secretion.MCC950 specifically blocks caspase-11-directed NLRP3 activation and IL-1β secretion upon stimulation of the non-canonical pathway. NLRC4-stimulated IL-1β and TNF-α secretion (as activated by Salmonella typhimurium) are not inhibited by MCC950 even at a concentration of 10 µM. MCC950 does not inhibit caspase-1 activation or IL-1β processing in response to S. typhimurium. The expression of pro-caspase-1 and pro-IL-1β in cell lysates is not substantially affected by MCC950 treatment[1].
MCC950 reduces Interleukin-1p (IL-1β) production and attenuates the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Pre-treatment with MCC950 reduces serum concentrations of IL-1β and IL-6 while it does not considerably decrease the amount of TNF-α. Treatment of mice with MCC950 delays the onset and reduced the severity of EAE. Intracellular cytokine staining and FACS analysis of brain mononuclear cells from mice sacrificed on day 22 shows modestly reduced frequencies of IL-17 and IFN-γ producing CD3+ T cells in MCC950 treated mice in comparison with PBS-treated mice. IFN-γ and particularly IL-17 producing cell numbers are also reduced in both the CD4+ and γδ+ sub-populations of CD3+ T cells[1].
MCC950是一种强效且选择性的NLRP3抑制剂，在BMDMs和HMDMs中的IC50分别为7.5和8.1纳摩尔。
MCC950可以在纳摩尔浓度下阻止NLRP3的典型和非典型激活。 MCC950特异性地抑制NLRP3而不是AIM2，NLRC4或NLRP1的激活。在小鼠骨髓源性巨噬细胞（BMDM）和人单核细胞衍生的巨噬细胞（HMDM）中测试了MCC950对NLRP3炎症小体激活的影响。在BMDM中，MCC950的IC50约为7.5 nM，在HMDM中具有类似的抑制能力（IC50 = 8.1 nM）。 MCC950还剂量依赖性地抑制IL-1β但不是TNF-α分泌。 MCC950特异性地阻断caspase-11定向的非经典途径刺激引起的NLRP3激活和IL-1β分泌。即使在10μm浓度下，也无法通过Salmonella typhimurium诱导NLRC4刺激引起IL-1β和TNF-α分泌来抑制MCC950。 MCC950不会通过S.typhimurium诱导抑制caspase-1活化或IL-1β加工反应。 经过McC95处理后，细胞裂解物中pro-caspase-1和pro-IL-1β的表达没有受到实质性影响[1]。
MCC950可以减少白细胞介素-1β（IL-1β）的产生，缓解实验性自身免疫脑脊髓炎（EAE）的严重程度，这是多发性硬化症的一种疾病模型。预先使用MCC950可降低血清中IL-1β和IL-6的浓度，但并不会显着降低TNF-α的数量。用MCC950治疗小鼠可以延迟EAE的发作时间，并减轻其严重程度。在第22天牺牲后对小鼠脑单个核细胞进行细胞因子染色和流式细胞分析显示，在与PBS处理组相比较下，接受MCC950治疗组CD3+ T 细胞中 IL-17 和 IFN-γ 产生频率略有降低。同时，在 CD4+ 和 γδ+ 亚群中也都减少了IFN-gamma和特别是IL-17 的产生[1]。
Reference:
[1]. Coll RC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015 Mar;21(3):248-55. [2]. Gan W, et al. The SGK1 inhibitor EMD638683, prevents Angiotensin II-induced cardiac inflammation and fibrosis by blocking NLRP3 inflammasome activation. Biochim Biophys Acta. 2017 Oct 3;1864(1):1-10. [3]. Zhang XY, et al. Propofol Does Not Reduce Pyroptosis of Enterocytes and Intestinal Epithelial Injury After Lipopolysaccharide Challenge. Dig Dis Sci. 2018 Jan;63(1):81-91. [4]. Qi Y, et al. NLRP3-dependent synaptic plasticity deficit in an Alzheimer’s disease amyloidosis model in vivo. Neurobiol Dis. 2018 Feb 23;114:24-30.
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Cell experiment: |
BMDM are seeded at 5×105/mL or 1×106/mL, HMDM at 5×105/mL and PBMC at 2×106/mL or 5×106/mL in 96 well plates. The following day the overnight medium is replaced and cells are stimulated with 10 ng/mL LPS from Escherichia coli serotype EH100 (ra) TLRgrad for 3 h. Medium is removed and replaced with serum free medium (SFM) containing DMSO (1:1,000), MCC950 (0.001-10 µM), glyburide (200 µM), Parthenolide (10 µM) or Bayer cysteinyl leukotriene receptor antagonist 1-(5-carboxy-2{3-[4-(3-cyclohexylpropoxy)phenyl]propoxy}benzoyl)piperidine-4-carboxylic acid (40 µM) for 30 min. Cells are then stimulated with inflammasome activators: 5 mM adenosine 5’-triphosphate disodium salt hydrate (ATP) (1 h), 1 µg/mL Poly(deoxyadenylic-thymidylic) acid sodium salt (Poly dA:dT) transfected with Lipofectamine 200 (3-4 h), 200 µg/mL MSU (overnight) and 10 µM nigericin (1 h) or S. typhimurium UK-1 strain. Cells are also stimulated with 25 µg/mL Polyadenylic-polyuridylic acid (4 h). For non-canonical inflammasome activation cells are primed with 100 ng/mL Pam3CSK4 for 4 h, medium is removed and replaced with SFM containing DMSO or MCC950 and 2 µg/mL LPS is transfected using 0.25% FuGENE for 16 h. Supernatants are removed and analysed using ELISA kits. LDH release is measured using the CytoTox96 non-radioactive cytotoxicity assay[1]. |
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Animal experiment: |
Mice[1] C57BL/6 mice are immunized subcutaneously with 150 µg of MOG peptide 35-55 emulsified in CFA containing 4 mg/mL (0.4.mg/mouse) of heat-killed MTB. Mice are injected i.p. with 500 ng pertussis toxin (PT: kaketsuken) on days 0 and 2. MCC950 is administered i.p. to mice (10 mg/kg) at induction of the disease, day 0, 1 and 2 and every 2 days thereafter. Control mice are administered vehicle (PBS) at the same time points. Mice are observed for clinical signs of disease daily (unblinded). Disease severity is scored as follows: no clinical signs, 0; limp tail, 1; ataxic gait, 2; hind limb weakness, 3; hind limb paralysis, 4; and tetra paralysis, 5. |
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References: [1]. Coll RC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015 Mar;21(3):248-55. |
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| Cas No. | 210826-40-7 | SDF | |
| 别名 | CP-456773; CRID3 | ||
| Canonical SMILES | O=S(C1=CC(C(C)(O)C)=CO1)(NC(NC2=C3CCCC3=CC4=C2CCC4)=O)=O | ||
| 分子式 | C20H24N2O5S | 分子量 | 404.48 |
| 溶解度 | DMSO : ≥ 28 mg/mL (69.22 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 | 2.4723 mL | 12.3616 mL | 24.7231 mL |
| 5 mM | 0.4945 mL | 2.4723 mL | 4.9446 mL |
| 10 mM | 0.2472 mL | 1.2362 mL | 2.4723 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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