NLRP3 inflammasome inhibitor - MCC950

NLRP3 inflammasome inhibitor

Inhibition of the NLRP3 inflammasome by MCC950

MCC950 is a potent and specific inhibitor of the NLRP3 (NOD-like receptor pyrin domain-containing protein 3, cryopyrin, or NALP3) inflammasome [1,2]. The multiprotein NLRP3 inflammasome complex is a key player in innate immunity. It participates in the production of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and IL-18, as well as leading to alarmin secretion and pyroptosis, a form of immunogenic cell death.

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Mode of action:

MCC950 blocks the release of IL‑1β induced by NLRP3 activators, such as nigericin, ATP, and MSU crystals [3,4]. It inhibits the NLRP3 inflammasome by directly targeting the NLRP3 NATCH domain and interfering with the Walker B motif function thus preventing NLRP3 conformational change and oligomerization [1,2]. In research models of inflammation, such as cryopyrin-associated periodic syndromes (CAPS) and myocardial infarction, MCC950 effectively inhibited NLRP3-induced IL-1β production [3-5]. Importantly, MCC950 is a specific inhibitor of the NLRP3 inflammasome.  It displays no effect on the AIM2, NLRC4, or NLRP1 inflammasomes [4].
 

Key features:

• A potent and specific inhibitor of the NLRP3 inflammasome
• InvitroFit™ grade: each lot is highly pure (≥98%) and functionally tested

Read our review on the NLRP3 inflammasome.

Download our Practical guide on Inflammasomes.

References:

1. Tapia-Abellán A. et al., 2019. MCC950 closes the active conformation of NLRP3 to an inactive state. Nature Chemical Biology. 15(6):560-4.
2. Coll R.C. et al., 2019. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nature Chemical Biology. 15(6):556-9.
3. Guo H. et al., 2015. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 21(7):677-87.
4. Coll RC. et al., 2015. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nature Med 21(3), 248-255.
5. van Hout GP. et al., 2016. The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur Heart J. ehw247.

Figures

MCC950 inhibits the NLRP3 inflammasome response in a dose-dependent manner.
THP1-Null2 cells, primed with LPS-EK (1 μg/ml for 3 h), were stimulated with MSU (150 µg/ml) and increasing concentrations of MCC950. After overnight incubation, IL-1β secretion was analyzed by adding 50 μl of supernatant from treated THP1-Null2 cells to HEK‑Blue™ IL‑1β cells. IL‑1β‑induced activation of NF‑κB was assessed by measuring the levels of SEAP in the supernatant of HEK-Blue™ IL-1β cells using QUANTI‑Blue™ Solution, a SEAP detection reagent, and by reading the optical density (OD) at 655 nm. Data are shown as percentage (%) inhibition.

Specifications

CAS number: 210826-40-7

Working concentration: 300 nM (121.34 ng/ml) to 10 μM (4.04 μg/ml) for cell culture assays

Solubility: DMSO (10 mg/ml)

Formula: C₂₀H₂₄N₂O₅S

Molecular weight: 404.48 g/mol

Quality control:

• Purity: ≥98% (UHPLC)
• The inhibitory activity of the product has been validated in inflammasome cellular assays using THP1-Null2 and HEK-Blue™ IL-1β cells.
• The absence of bacterial contamination (e.g. lipoproteins and endotoxins) is confirmed using HEK-Blue™ TLR2 and HEK-Blue™ TLR4 cells.

Contents

MCC950 is provided as a translucent film. It is available in two quantities:

• inh-mcc: 10 mg
• inh-mcc-5: 5 x 10 mg

MCC950 is shipped at room temperature.

Upon receipt, store at -20°C.

Details

The NLRP3 Inflammasome:

The NLRP3 inflammasome is an innate immune sensor that is activated by a two-step process; a first signal (‘priming’) provided mainly by bacterial components or endogenous cytokines involves NF-κB induction, while the second signal provided by a wide array of stimuli including microbial toxins, endogenous molecules or crystalline substances and leads to inflammasome assembly and activation [1, 2].  This triggers inflammasome multimerization and caspase-1 activation with the subsequent cleavage of interleukin-1β (IL-1β)/IL-18 and the pore-forming protein Gasdermin D (GSDMD) into their active forms. Additionally, the activation of the inflammasome also leads to alarmin secretion and pyroptosis, a form of immunogenic cell death.

1. Swanson K.V. et al., 2019. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19:477.
2. Groslambert M. & Py B. 2018. Spotlight on the NLRP3 inflammasome pathway. J. Inflamm. Res. 11:359.

Chemical structure of MCC950:

Citations