Belnacasan (VX-765)

For research use only.

Catalog No.S2228

69 publications

Belnacasan (VX-765) Chemical Structure

CAS No. 273404-37-8

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.

Selleck's Belnacasan (VX-765) has been cited by 69 publications

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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.
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

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]

Assay
Methods Test Index PMID
Western blot
Bax / Bcl-2 / caspase-3 / caspase-1 / caspase-11 / GSDMD-N / GAPDH; 

PubMed: 32865056     


Analysis of protein expression in P12 cells induced by lipopolysaccharide and adenosine triphosphate treatment and exposed to the caspase inhibitors, Belnacasan (Beln) and Wedelolactone (Wede). b) The expression of apoptosis-related proteins was analyzed through western blotting. c) The expression of proteins mediating pyroptosis was analyzed through western blotting.

Cyto c / Tubulin; 

PubMed: 30846986     


NLRP3 and caspase-8 are required for ERS-induced mitochondrial damage. (B) Immunoblot analysis of cytochrome c in the cytosolic extracts from BMDMs treated with no inhibitor or belnacasan for 1 h and then infected with M. bovis (MOI 10) for 48 h.

Bid / tBid / Tubulin; 

PubMed: 30846986     


(H) Immunoblot analysis of Bid in lysates of BMDMs treated with or without belnacasan for 1 h and then infected for 48 h with M. bovis (MOI 10).

32865056 30846986
IHC
HE staining / TUNEL; 

PubMed: 31903272     


Caspase-1 is essential in mtDNA-induced lung inflammation and injury. (A) Belnacasan significantly decreased mtDNA-induced pulmonary inflammation.

31903272
Immunofluorescence
GSDMD-NT; 

PubMed: 32865056     


Immunofluorescence analysis of the subcellular distribution of GSDMD-NT in PC12 cells induced by lipopolysaccharide and adenosine triphosphate treatment and then exposed to the caspase inhibitors, Belnacasan (Beln) and Wedelolactone (Wede).

32865056
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]

Protocol

Animal Research:[1]
- Collapse
  • Animal Models: Collagen-induced arthritis mouse model.
  • Dosages: ≤200 mg/kg
  • Administration: Administered via p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL warmed (196.46 mM)
Water Insoluble
Ethanol '100 mg/mL warmed
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+30% PEG 300+ddH2O
For best results, use promptly after mixing.
5mg/mL

* 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.

Chemical Information

Molecular Weight 509
Formula

C24H33ClN4O6

CAS No. 273404-37-8
Storage powder
in solvent
Synonyms N/A
Smiles CCOC1C(CC(=O)O1)NC(=O)C2CCCN2C(=O)C(C(C)(C)C)NC(=O)C3=CC(=C(C=C3)N)Cl

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01501383 Terminated Drug: VX-765 Part A|Drug: Placebo|Drug: VX-765 Part B Epilepsy Vertex Pharmaceuticals Incorporated December 2011 Phase 2

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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID