In vitro: 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.
In vivo: 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.
Front Pharmacol. 2021 May 31;12:599393.
Neurochem Res. 2020 Sep;45(9):2020-2031.
MCC950 Inhibits NLRP3 Inflammasome and Alleviates Axonal Injures in Early Stages of Diffuse Axonal Injury in Rats
MCC950 purchased from AbMole
Cell Rep. 2020 May 19;31(7):107667.
hGBP1 Coordinates Chlamydia Restriction and Inflammasome Activation through Sequential GTP Hydrolysis
MCC950 purchased from AbMole
|Source||Cell Reports 2020 May. Figure 3. MCC950 (Abmole Bioscience, USA)|
|Method||C. trachomatis infection|
|Cell Lines||Human primary monocyte-derived macrophages|
|Incubation Time||1 h|
|Results||MCC950 treatment largely abolished infection-induced IL-1b secretion and pyroptosis.|
|Cell lines||BMDM cell|
|Preparation method||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.|
|Incubation time||16 h|
|Animal models||C57BL/6 mice|
|Formulation||dissolved in DMSO and diluted with PBS|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||28 mg/mL in DMSO|
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CY-09 is a selective and direct NLRP3 inhibitor.
|CP-456773 sodium salt
CP-456773 sodium salt (MCC950) was found to act as a cytokine release inhibitory drug and inhibitor of the NLRP3 inflammasome.
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