Belnacasan (VX-765)

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.

Belnacasan (VX-765) Chemical Structure

Belnacasan (VX-765) Chemical Structure

CAS: 273404-37-8

Selleck's Belnacasan (VX-765) has been cited by 127 publications

Purity & Quality Control

Batch: Purity: 99.99%
99.99

Belnacasan (VX-765) Related Products

Signaling Pathway

Choose Selective Caspase Inhibitors

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.
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
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
NCT01501383 Terminated
Epilepsy
Vertex Pharmaceuticals Incorporated
December 2011 Phase 2

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)

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


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In vivo
Batch:

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In vivo Formulation Calculator

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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.
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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

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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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