Caspase-1, also called as interleukin-converting enzyme (ICE), is the cysteine protease able to cleave pro-IL-1 and pro-IL-18 to the active cytokines IL-1 and IL-18, both of which are important to the acute and chronic stages of inflammatory immune responses. VX-765 is the prodrug of VRT-043198, which is a selective inhibitor of caspase-1 subfamily caspases with Ki value of 0.8nM for caspase-1 and <0.6nM for caspase-4 (measured by protease enzyme assays), respectively, and exhibits 100- to 10,000-fold selectivity against other caspase-3 and -6 to -9. As its inactivation against caspase-1, VRT-043198 inhibited LPS-stimulated release of cytokines, IL-1,from both PBMCs and whole blood with IC50 values of 0.67μM and 1.9μM, respectively. Also, VRT-043198 could dose-dependently inhibit SAC(S. aureusCowan strain 1)-stimulated release of IL-1, IL-18 and IFN-γ with IC50 values of 0.87μM, 2.8μM and 5.6μM, respectively, from human PBMCs, but not TNF-α. It was found that VRT-043198 lacked potent anti-apoptotic activity as its low potency against caspase-9, but effective on Fas-induced apoptosis in the Jurkat human T-cell line, where initiation of the apoptosis cascade is mediated by caspase-8 activity. When orally dosed mice with VX-765, it can be efficiently converted to VRT-043198. A single dose of VX-765 at dose of 50-200mg/kg 1h before LPS injection reduced serum IL-1 levels up to 60% after 2.5h in peripheral blood samples from LPS-injected mice. Oral administration of VX-765 at dose of 25, 50 and 100 mg/kg, at 24 and 36 h after challenge by oxazolone, caused reduced production of inflammatory mediators in biopsy samples from oxazolone-challenged mouse ears, including IL-1, IL-18, IFN-γ, nitric oxide and MIP-2 (at all dose), MCP-1 and MIP-1α(50 and mg/kg), IL-4 and myeloperoxidase (100mg/kg). VX-765 at dose of 10, 25, 50, or 100 mg/kg, b.i.d., for 24 days, could significantly reduce the forepaw inflammation in the mouse CIA model, as well as reduced disease severity in models of collagen-induced-rheumatoid arthritis, suggesting that suggest that VX-765 may be a novel cytokine inhibitor and useful for treatment of inflammatory diseases[1]. VX-765 prevented pyroptosis by prevention of GSDMD cleavage, a cleavage target of caspase-1 and caspase-11. The differential ability of VX-765 and Ac-YVAD-cmk to inhibit pyroptosis was reflected in the prevention of GSDMD cleavage by VX-765, but not by Ac-YVAD-cmk[5].
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