Belnacasan (VX-765)

Catalog No.S2228 Batch:S222807

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Technical Data

Formula

C24H33ClN4O6
Molecular Weight 509 CAS No. 273404-37-8
Solubility (25°C)* In vitro DMSO 100 mg/mL (196.46 mM)
Ethanol 100 mg/mL (196.46 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description Belnacasan (VX-765) is a potent and selective inhibitor of caspase-1 with Ki of 0.8 nM in a cell-free assay. Phase 2.
Targets
Caspase-4 [1]
(Cell-free assay)		 Caspase-1 [1]
(Cell-free assay)
<0.6 nM(Ki) 0.8 nM(Ki)
In vitro

VX-765 is an orally absorbed prodrug of VRT-043198, which exhibits potent inhibition against ICE/caspase-1 and caspase-4 with Ki of 0.8 nM and less than 0.6 nM, respectively. And VRT-043198 also inhibits IL-1β release from both PBMCs and whole blood with IC50 of 0.67 μM and 1.9 μM, respectively. [1]
In vivo

In collagen-induced arthritis mouse model, VX-765 (200 mg/kg) inhibits LPS-induced IL-1β production by about 60%, and results in a dose-dependent, statistically significant reduction in the inflammation scores and effective protection from joint changes. [1]

In vivo, VX-765 blocks kindling epileptogenesis in rats by preventing IL-1β increase in forebrain astrocytes without significant effect on afterdischarge duration. [2]

In the mouse model of acute seizures, VX-765 (50 mg/kg-200 mg/kg) produces the anticonvulsant effect by delaying the time to onset of the first seizure and decreasing the number of seizures as well as their total duration by average 50% and 64%. [3]

In adult rats with genetic absence epilepsy (GAERS), VX-765, after the 3rd drug injection, significantly reduces the cumulative duration and number of spike-and-wave discharges (SWDs) by 55% on average by selectively blocking IL-1β biosynthesis. [4]
Features A potent and selective inhibitor of interleukin-converting enzyme/caspase-1.

Protocol (from reference)

Kinase Assay:

[1]
  • Protease Enzyme Assays

    Enzyme inhibition is assayed by tracking of the rate of hydrolysis of an appropriate substrate labeled with either p-nitroaniline or aminomethyl coumarin (AMC) as follows: ICE/caspase-1, suc-YVAD-p-nitroanilide; caspase-4, Ac-WEHD-AMC; caspase-6, Ac-VEID-AMC; caspase-3, -7, -8, and -9, Ac-DEVD-AMC; and granzyme B, Ac-IEPD-AMC. Enzymes and substrates are incubated in a reaction buffer [10 mM Tris, pH 7.5, 0.1% (w/v) CHAPS, 1 mM dithiothreitol, and 5% (v/v) dimethyl sulfoxide] for 10 minutes at 37 °C. Glycerol is added to the buffer at 8% (v/v) for caspase-3, -6, and -9 and granzyme B to improve stability of enzymes. The rate of substrate hydrolysis is monitored using a fluorometer
Cell Assay:

[5]
  • Cell lines

    PBMCs

  • Concentrations

    0.7 µM

  • Incubation Time

    30 minutes

  • Method

    PBMCs were pre-treated with VX-765 for 30 minutes before exposure to LPS.
Animal Study:

[1]
  • Animal Models

    Collagen-induced arthritis mouse model.

  • Dosages

    ≤200 mg/kg

  • Administration

    Administered via p.o.

Customer Product Validation

Data from [Data independently produced by , , Cell, 2018, 175(2):442-457]

Data from [Data independently produced by , , Mucosal Immunol, 2015, 10.1038/mi.2015.44]

Data from [Data independently produced by , , Mucosal Immunol, 2016, 9(1):124-36]

Data from [Data independently produced by , , Front Immunol, 2016, 7:536.]

Selleck's Belnacasan (VX-765) has been cited by 156 publications

Selenium deficiency exacerbates ROS/ER Stress mediated pyroptosis and ferroptosis induced by bisphenol A in chickens thymus [ Journal of Environmental Sciences, 2025, Volume 148] PubMed: none
Combined targeting of GPX4 and BCR-ABL tyrosine kinase selectively compromises BCR-ABL+ leukemia stem cells [ Mol Cancer, 2024, 23(1):240] PubMed: 39465372
Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application [ Nat Commun, 2024, 15(1):8266] PubMed: 39327452
Platelet transcription factors license the pro-inflammatory cytokine response of human monocytes [ EMBO Mol Med, 2024, 10.1038/s44321-024-00093-3] PubMed: 38977927
Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation [ Cell Rep, 2024, 43(9):114736] PubMed: 39277863
Glucose metabolite methylglyoxal induces vascular endothelial cell pyroptosis via NLRP3 inflammasome activation and oxidative stress in vitro and in vivo [ Cell Mol Life Sci, 2024, 81(1):401] PubMed: 39269632
Blocking CIRP protects against acute pancreatitis by improving mitochondrial function and suppressing pyroptosis in acinar cells [ Cell Death Discov, 2024, 10(1):156] PubMed: 38538578
Bacillus cereus cereolysin O induces pyroptosis in an undecapeptide-dependent manner [ Cell Death Discov, 2024, 10(1):122] PubMed: 38458999
RVFV virulence factor NSs triggers the mitochondrial MCL-1-BAK axis to activate pathogenic NLRP3 pyroptosis [ PLoS Pathog, 2024, 20(8):e1012387] PubMed: 39213434
Host E3 ubiquitin ligase ITCH mediates Toxoplasma gondii effector GRA35-triggered NLRP1 inflammasome activation and cell-autonomous immunity [ mBio, 2024, e0330223.] PubMed: 38376248

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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