VX-765

Caspase-1 inhibitor

VX-765 is an orally absorbed prodrug of VRT-043198, a potent and selective inhibitor of caspases belonging to the ICE/caspase-1 subfamily [1].

VX-765 is converted to VRT-043198 under the action of plasma and liver esterases. The active metabolite of VX-765 exhibits potent inhibition of caspase-1 and caspase-4 and at least 100-fold lower potency against other non-ICE subfamily caspases.

VX-765 was shown to reduce the production of IL-1β and IL-18 both in vitro and in vivo in correlation with tissue-protective effects in animal models of inflammatory disease [1].

VX-765 was found in a phase II a trial to be safe and well tolerated.

Recent data demonstrate that VX-765 prevents CD4 T-cell pyroptotic death in a dose-dependent manner in HIV-infected lymphoid tissues [2].

References:

1. Wannamaker W. et al., 2007. (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J Pharmacol Exp Ther. 321(2):509-16.
2. Doitsh G. et al., 2014. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature. 505(7484):509-14.

Figures

IL-1β production in THP1 cells following their stimulation with CPPD, Alhydrogel and Chitosan
Cells treated or not with VX-765 (100µM) and primed with LPS (1 μg/ml) were stimulated with CPPD (50µg/ml),  Alhydrogel (1/100) and Chitosan (100µg/ml). After 24h incubation, the supernatants were added 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 the QUANTI-Blue™ assay.

Lucia production  in THP1-Lucia™ ISG cells following their stimulation with human IFNα2a, 2' 3'-cGAMP and Poly(dA:dT) / LyoVec™.
Cells treated or not with VX-765 (100µM) were stimulated with IFNα2a (30UI/ml),  2' 3'-cGAMP (20µg/ml) and Poly(dA:dT) / LyoVec™ (500ng/ml). After 24h incubation, the levels of Lucia in the supernatant of THP1-Lucia™ ISG cells using the QUANTI-Luc™ assay.

Seap production  in THP1-Dual cells following their stimulation with LPS-EK (10ng/ml), 2' 3'-cGAMP (10µg/ml) and Pam3CSK4 (100 ng/ml).
After 24h incubation, the levels of SEAP in the supernatant of THP1-Dual cells is determined using the QUANTI-Blue™ assay.

VX-765 is converted to VRT-043198 under the action of plasma and liver esterases.

Specifications

CAS number: 273404-37-8

Chemical Name: (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide

Solubility: 100 mg/ml (200 mM) in DMSO or ethanol

Formula: C₂₄H₃₃ClN₄O₆

Molecular weight: 509

Purity: >97% (HPLC)

Quality control

• The absence of bacterial contamination (e.g. endotoxins and peptidoglycans) is controlled using HEK-Blue™ TLR2 and HEK-Blue™ TLR4 cells.
• The inhibitory activity of the product is validated using an in vitro inhibition of caspase-1 assay.

Contents

VX-765 is available in 2 quantities:

• 10 mg VX-765 (#inh-vx765-1)
• 5 x 10 mg VX-765 (#inh-vx765-5)

VX-765 is shipped at room temperature.

Upon receipt, store at -20°C for up to 2 years.

 Product is provided as a translucent film.