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MCC950 (CP-456773) (Synonyms: CP 456,773)

カタログ番号GC31644

MCC950 (CP-456773) (CP-456773; CRID3) は、BMDM と HMDM でそれぞれ 7.5 と 8.1 nM の IC50 を持つ強力で選択的な NLRP3 阻害剤です。

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MCC950 (CP-456773) 化学構造

Cas No.: 210826-40-7

サイズ 価格 在庫数 個数
10mM (in 1mL DMSO)
$56.00
在庫あり
5mg
$50.00
在庫あり
10mg
$63.00
在庫あり
50mg
$260.00
在庫あり
100mg
$483.00
在庫あり

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Sample solution is provided at 25 µL, 10mM.

Product has been cited by 9 publications

Product Documents

Quality Control & SDS

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Protocol

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].

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.

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.
[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.

Background

MCC950は、BMDMsおよびHMDMsにおいてIC50がそれぞれ7.5nMと8.1nMの強力で選択的なNLRP3阻害剤です。

MCC950は、ナノモル濃度でカノニカルおよび非カノニカルNLRP3活性化を阻害します。MCC950は、特にNLRP3のみを抑制し、AIM2、NLRC4、またはNLRP1の活性化には影響しません。MCC950のNLRP3インフラマソーム活性化への影響は、マウス骨髄由来マクロファージ(BMDM)および人間単球由来マクロファージ(HMDM)でテストされます。BMDMにおけるMCC950のIC50は約7.5 nMであり、HMDMでも同様の抑制能力があります(IC50=8.1 nM)。 MCC950はIL-1β分泌を投薬量依存的に阻害しますが、TNF-α分泌を阻害しません。 MCC950は特定的にcaspase-11指向性NLRP3活性化と非カノニカル経路刺激時のIL-1β分泌をブロックします。サルモネラ・チフィムリウム感染時に誘発されたNLRC4刺激型IL-1βおよびTNF-α分泌も10μmでも完全な抑制効果は示しません。 MCC950は、S. typhimuriumに対する応答でのcaspase-1活性化またはIL-1β処理を阻害しません。細胞リザート中のpro-caspase-1およびpro-IL-1βの発現にMCC950投与が大きな影響を与えることはありません[1]。

MCC950は、多発性硬化症の疾患モデルである実験的自己免疫脳脊髄炎(EAE)の重症度を軽減し、インターロイキン-1p(IL-1β)の産生を低下させます。 MCC950の予防投与により、IL-1βおよびIL-6の血清濃度が低下する一方で、TNF-α量はあまり減少しません。 MCC950でマウスを治療すると、EAEの発現が遅れて重症度も低下します。 22日目に生贄となったマウスから得られた脳単核細胞の細胞内サイトカイン染色およびFACS解析では、MCC950処理されたマウスではPBS処理されたマウスに比べてCD3 + T細胞中でIL-17およびIFN-gamma産生頻度がわずかに低下しています。 IFN-gamma特にIL-17産生細胞数は、CD3 + T細胞のCD4 +およびγδ+サブポピュレーションでも減少しています[1]。

[1]. Coll RCら。炎症性疾患の治療のためのNLRP3インフラマソームの小分子阻害剤。Nat Med. 2015年3月;21(3):248-55。[2]. Gan Wら。SGK1阻害剤EMD638683は、NLRP3インフラマソーム活性化をブロックすることにより、アンジオテンシンII誘発性心臓炎および線維化を予防します。Biochim Biophys Acta. 2017年10月3日;1864(1):1-10。[3]. Zhang XYら。プロポフォールは、リポ多糖誘発後腸管上皮細胞のパイロプトーシスおよび腸管上皮損傷を減少させません。Dig Dis Sci. 2018年1月;63(1):81-91.[4]. Qi Yら。アルツハイマー型アミロイドーシスモデルにおけるNLRP3依存性シナプス可塑性欠損 vivoでNeurobiol Dis. 2018年2月23日;114:24-30。

Chemical Properties

Cas No. 210826-40-7 SDF
同義語 CP 456,773
Canonical SMILES O=S(C1=CC(C(C)(O)C)=CO1)(NC(NC2=C3CCCC3=CC4=C2CCC4)=O)=O
Formula C20H24N2O5S M.Wt 404.48
溶解度 DMSO : ≥ 28 mg/mL (69.22 mM) Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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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
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    MCC950 (CP-456773) - GlpBio

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