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

Catalog No.GC31644

MCC950 (CP-456773) (CP-456773; CRID3) est un inhibiteur puissant et sélectif de NLRP3 avec des IC50 de 7,5 et 8,1 nM dans les BMDM et les HMDM, respectivement.

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MCC950 (CP-456773) Chemical Structure

Cas No.: 210826-40-7

Taille Prix Stock Qté
10mM (in 1mL DMSO)
56,00 $US
En stock
5mg
50,00 $US
En stock
10mg
63,00 $US
En stock
50mg
260,00 $US
En stock
100mg
483,00 $US
En stock

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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 est un inhibiteur puissant et sélectif de NLRP3 avec des IC50 de 7,5 et 8,1 nM dans les BMDMs et HMDMs, respectivement.

MCC950 bloque l'activation canonique et non-canonique de NLRP3 à des concentrations nanomolaires. MCC950 inhibe spécifiquement l'activation de NLRP3 mais pas AIM2, NLRC4 ou NLRP1. L'effet de MCC950 sur l'activation du complexe inflammasome NLRP3 est testé dans les macrophages dérivés de la moelle osseuse (BMDM) chez la souris et dans les macrophages dérivés des monocytes humains (HMDM). L'IC50 de MCC950 dans BMDM est d'environ 7,5 nM, tandis que dans HMDM il a une capacité inhibitrice similaire (IC50 = 8,1 nM). MCC950 inhibe également dose-dépendamment la sécrétion d'IL-1β mais pas celle du TNF-α. MCC950 bloque spécifiquement l'activation dirigée par caspase-11 de NLRP3 et la sécrétion d'IL-1β lorsqu'elle est stimulée par la voie non-canonique. La sécrétion d'IL-1β et TNF-α stimulée par NLRC4 (comme activée par Salmonella typhimurium) n'est pas inhibée par MCC950 même à une concentration de 10 μm. MCC950 n'inhibe pas l'activation de caspase-1 ou le traitement d'IL-1β en réponse à S. typhimurium. L’expression des pro-caspases 1 et pro IL - 1 β dans les lysats cellulaires n'est pas substantiellement affectée par le traitement avec le médicament MCC950[1].

MCC950 réduit la production d'Interleukine-1p (IL-1β) et atténue la gravité de l'encéphalomyélite auto-immune expérimentale (EAE), un modèle de maladie de la sclérose en plaques. Le prétraitement avec MCC950 réduit les concentrations sériques d'IL-1β et d'IL-6, tandis qu'il ne diminue pas considérablement la quantité de TNF-α. Le traitement des souris avec MCC950 retarde l'apparition et réduit la gravité de l'EAE. La coloration intracellulaire des cytokines et l'analyse FACS des cellules mononucléaires du cerveau provenant de souris sacrifiées le jour 22 montrent une fréquence modérément réduite des cellules T CD3+ produisant IL-17 et IFN-gamma chez les souris traitées par MCC950 par rapport aux souris traitées au PBS. Les nombres de cellules produisant IFN-gamma et particulièrement IL-17 sont également réduits dans les sous-populations CD4+ et γδ+ des cellules T CD3+.

[1]. Coll RC, et al. Un inhibiteur de petite molécule de l'inflammasome NLRP3 pour le traitement des maladies inflammatoires. Nat Med. 2015 Mar;21(3):248-55. [2]. Gan W, et al. L'inhibiteur SGK1 EMD638683 prévient l'inflammation cardiaque induite par l'angiotensine II et la fibrose en bloquant l'activation de l'inflammasome NLRP3. Biochim Biophys Acta. 2017 Oct 3;1864(1):1-10. [3]. Zhang XY, et al. Le propofol ne réduit pas la pyroptose des entérocytes ni les dommages épithéliaux intestinaux après un défi au lipopolysaccharide. Dig Dis Sci. Janvier 2018;63(1):81-91.[4]. Qi Y, et al.Déficit de plasticité synaptique dépendant du NLRP3 dans un modèle d'amyloïdose liée à la maladie d'Alzheimer in vivo.Neurobiol Dis.Février 2018;114:24-30

Chemical Properties

Cas No. 210826-40-7 SDF
Synonymes 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
Solubility 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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Average Rating: 5 ★★★★★ (Based on Reviews and 28 reference(s) in Google Scholar.)

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