MCC950

Biological Activity

In vitro: MCC950 (CP-456773) 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 (CP-456773) 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.

Product Citations

• 

  Experimental Lung Research. 2022 Apr-Aug;48(4-6):168-177.

  Low tidal volume ventilation alleviates ventilator-induced lung injury by regulating the NLRP3 inflammasome
  MCC950 purchased from AbMole

• 

  BMC Neurosci. 2022 Nov 27;23(1):70.

  NLRP3 inflammasome regulates astrocyte transformation in brain injury induced by chronic intermittent hypoxia
  MCC950 purchased from AbMole

• 

  Front Cell Infect Microbiol. 2022 Aug 9;12:925435.

  Outer membrane vesicles of Porphyromonas gingivalis trigger NLRP3 inflammasome and induce neuroinflammation, tau phosphorylation, and memory
  MCC950 purchased from AbMole

• 

  J Inflamm Res. 2022 Sep 13;15:5309-5326.

  P2X7R-NEK7-NLRP3 Inflammasome Activation: A Novel Therapeutic Pathway of Qishen Granule in the Treatment of Acute Myocardial Ischemia
  MCC950 purchased from AbMole

• 

  Biomed J. 2023 Feb 7;S2319-4170(23)00004-5.

  Inhibition of NLRP3 attenuates sodium dextran sulfate-induced inflammatory bowel disease through gut microbiota regulation
  MCC950 purchased from AbMole

• 

  J Hazard Mater. 2022 Oct 5;439:129502.

  Polystyrene nanoparticle exposure supports ROS-NLRP3 axis-dependent DNA-NET to promote liver inflammation
  MCC950 purchased from AbMole

• 

  J Neuroimmune Pharmacol. 2022 Jan 3.

  Inhibition of Microglial NLRP3 with MCC950 Attenuates Microglial Morphology and NLRP3/Caspase-1/IL-1β Signaling In Stress-induced Mice
  MCC950 purchased from AbMole

• 

  Mol Cell Toxicol. 2022 Jan 10;1-11.

  Ferulic acid exhibits anti-inflammatory effects by inducing autophagy and blocking NLRP3 inflammasome activation
  MCC950 purchased from AbMole

• 

  Front Pharmacol. 2021 May 31;12:599393.

  Histamine H 3 Receptor Signaling Regulates the NLRP3 Inflammasome Activation in C2C12 Myocyte During Myogenic Differentiation
  MCC950 purchased from AbMole

• 

  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

Customer Product Validations & Biological Datas

	Source	Cell Reports 2020 May. Figure 3. MCC950 (Abmole Bioscience, USA)
	Method	C. trachomatis infection
	Cell Lines	Human primary monocyte-derived macrophages
	Concentrations	300 nM
	Incubation Time	1 h
	Results	MCC950 treatment largely abolished infection-induced IL-1b secretion and pyroptosis.

Protocol (for reference only)

Cell Experiment
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.
Concentrations	0.001-10 µM
Incubation time	16 h

Animal Experiment
Animal models	C57BL/6 mice
Formulation	dissolved in DMSO and diluted with PBS
Dosages	10 mg/kg
Administration	i.p.

Chemical Information

Molecular Weight	404.48
Formula	C20H24N2O5S
CAS Number	210826-40-7
Solubility (25°C)	28 mg/mL in DMSO
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

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 K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Cong-Fa Huang, et al. J Exp Clin Cancer Res. NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma

[2] Rebecca C Coll, et al. Nat Med. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases