CASPASE-1/4 INHIBITOR VX-765

General description

An enhanced cell-permeable, non-toxic, orally available masked aspartaldehyde prodrug that is converted to its active metabolite, VRT-043198, both in vitro and in vivo via hydrolytic cleavage by esterases. The active metabolite displays anti- inflammatory and anticonvulsant properties. Binds to the active site of caspase-1 and caspase-4 with high affinity to inhibit their activity (K_i = 800 pM and 600 pM, respectively). Does not affect the activities of trypsin, cathepsin B and has much reduced effect on other caspases (K_i = 100 nM to 21.5 µM) and granzyme B (K_i = 900 nM). Recently shown to inhibit pyroptosis and prevent CD4 T-cell death by HIV-1. Also shown to block the release of lipopolysaccharide- induced IL-1β and IL-18 in human PBMC (IC₅₀ = 700 pM). Blocks Staphalococcus aureus - Cowen strain I-stimulated production of IL-1β, IL-18, and IFN-γ in human PBMCs (IC₅₀ = 870 nM and 2.8 and 5.6 µM, respectively), but does not affect the TNF-α levels (IC₅₀ >50 µM). Appears to cross the blood brain barrier to block seizure-induced IL-1β production and delay the onset and reduces the duration of seizures in rats (50 mg/kg, i.p.).

Please note that the molecular weight for this compound is batch-specific due to variable water content.

The cell-permeable prodrug of the caspase-1/4-selective inhibitor VRT-43198 (K_i in nM = <0.6/Caspase-4, 0.8/Caspase-1, 100/Caspase-8, 560/Caspase-6, 1,030/Caspase-9, 9,000/Granzyme B, 16,000/Caspase-7, 21,500/Caspase-3; IC₅₀ >100 µM against Cathepsin B & Trypsin). In addition to inhibiting LPS-induced IL-1β production in primary human PBMC cultures (IC₅₀ ~1 µM), VX-765 is also effective in preventing HIV infection-induced IL-1β production and pyroptosis of CD4 T cells in human lymphoid aggregate cultures (HLAC; CD4 population = 29.2% in non-infected control cultures, 8.3% vs. 30.2% in infected cultures with or without 5 µM VX-765). VX-765 is orally available in mice (Blood C_max = 0.78 µg/mL = 1.53 µM; T_max = 1.0 h; AUC_last = 2.06 µg · h/mL; 84 mg/kg, p.o.) and shown to display in vivo anti-inflammatory efficacy against LPS-induced plasma IL-1β production (ED_max = 100 mg/kg, p.o.), Oxazolone-induced delayed-type hypersensitivity (ED_max = 50 mg/kg, p.o.), collagen-induced arthritis (ED_max = 100 mg/kg, p.o.). When administered via intraperitoneal injection, VX-765 is also demonstrated to suppress the severity of seizure induction (ED_max = 50 mg/kg i.p.) among rats receiving kainic acid via intracerebroventricular injection.

Biochem/physiol Actions

Cell permeable: yes

Primary Target
caspase-1/4

Reversible: yes

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 1 month at -20°C.

Use only fresh DMSO for reconstitution.

Other Notes

Doitsh, G., et al. 2014. Nature505, 509.
Wannamaker, W., et al. 2007. J. Pharmacol. Exp. Ther.321, 509.

Ravizza, T., et al. 2006. Epilepsia47, 1160.
Stack, J.H., et al. 2005. J. Immunol.175, 2630.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany