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Belnacasan (VX-765)

Name: Belnacasan (VX-765)
Brand: Selleck Chemicals
SKU: S2228
Rating: 5 (136 reviews)

Catalog No.S2228 Purity:99.99%

Belnacasan (VX-765) is a potent and selective inhibitor of caspase-1 with K_i of 0.8 nM in a cell-free assay. Phase 2.

Belnacasan (VX-765) Chemical Structure

CAS No. 273404-37-8

Purity & Quality Control

Batch: Purity: 99.99%

99.99

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Signaling Pathway

Caspase Signaling Pathway

Biological Activity

Description

Belnacasan (VX-765) is a potent and selective inhibitor of caspase-1 with K_i of 0.8 nM in a cell-free assay. Phase 2.

Features

A potent and selective inhibitor of interleukin-converting enzyme/caspase-1.

Targets

Caspase-4 ^[1] (Cell-free assay)	Caspase-1 ^[1] (Cell-free assay)
<0.6 nM(Ki)	0.8 nM(Ki)

In vitro
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]
Kinase Assay	Protease Enzyme Assays
Kinase Assay	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 Research	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.
Experimental Result Images	Methods	Biomarkers	Images	PMID
	Western blot	Bax / Bcl-2 / caspase-3 / caspase-1 / caspase-11 / GSDMD-N / GAPDH Cyto c / Tubulin Bid / tBid / Tubulin		32865056
	IHC	HE staining / TUNEL		31903272
	Immunofluorescence	GSDMD-NT		32865056

In Vivo
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]
Animal Research	Animal Models	Collagen-induced arthritis mouse model.
	Dosages	≤200 mg/kg
	Administration	Administered via p.o.

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT01501383	Terminated	Epilepsy	Vertex Pharmaceuticals Incorporated	December 2011	Phase 2

References

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Chemical Information & Solubility

Molecular Weight	509	Formula	C₂₄H₃₃ClN₄O₆
CAS No.	273404-37-8	SDF	Download Belnacasan (VX-765) SDF
Smiles	CCOC1C(CC(=O)O1)NC(=O)C2CCCN2C(=O)C(C(C)(C)C)NC(=O)C3=CC(=C(C=C3)N)Cl
Storage (From the date of receipt)	3 years-20°Cpowder	Storage of Stock Solutions Aliquot the stock solutions to avoid repeated freeze-thaw cycles	1 year-80°Cin solvent
Storage (From the date of receipt)	3 years-20°Cpowder		1 month-20°Cin solvent

In vitro
Batch:

DMSO : 100 mg/mL ( (196.46 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 100 mg/mL

Water : Insoluble

Molecular Weight Calculator

In vivo Batch: Add solvents to the product individually and in order.					In vivo Formulation Calculator
	Clear solution	5% DMSO 1 95% Corn oil	1.25mg/ml (2.46mM)	Taking the 1 mL working solution as an example, add 50 μL of 25 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results.	In vivo Formulation Calculator
Clear solution	5%DMSO 1 40%PEG 300 2 5%Tween80 3 50% ddH2O	5.0mg/ml (9.82mM)	Taking the 1 mL working solution as an example, add 50 μL of 100 mg/mL clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify; add 50 μL of Tween-80 to the above system, mix evenly to clarify; Then continue to add 500 μL ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.
Clear solution	5% DMSO 1 40% PEG 300 2 5%Tween80 3 50%ddH2O	5.0mg/ml (9.82mM)	Taking the 1 mL working solution as an example, add 50 μL of 100 mg/ml clarified DMSO stock solution to 400 μL PEG300, mix evenly to clarify it; add 50 μL Tween80 to the above system, mix evenly to clarify it; then continue to add 500 μL ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

Preparing Stock Solutions

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
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Dilution Calculator Molecular Weight Calculator

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)

Dosage: mg/kg Average weight of animals: g Dosing volume per animal:μL Number of animals:

Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

Calculation results:

Working concentration: mg/ml;

Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such
as vortex, ultrasound or hot water bath can be used to aid dissolving.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

Tel: +1-832-582-8158 Ext:3
If you have any other enquiries, please leave a message.

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Frequently Asked Questions

Question 1:
The recommended dose of VX-765 is 100mg/kg p.o. in 25% cremophor EL in water. Is VX0765 directly soluble at 10mg/ml in 25% cremophor in water? How to formulate it for in vivo use in mice?

Answer:
You can prepare 25% cremophor EL in water first and then directly resuspend VX-765 powder in the vehicle. The powder may not be fully dissolved, but the suspension is stable and can be used for gavage feeding.

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