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].
VX-765 细胞实验
Cell Line
Concentration
Treated Time
Description
References
neural progenitor cells
10 μM
2 h
To evaluate the effect of VX-765 on mitochondrial respiration in neural progenitor cells, results showed that the oxygen consumption rate (OCR) was significantly reduced in the VX-765 treated group
Adv Sci (Weinh). 2024 Sep;11(35):e2402285.
BMSCs-derived beige adipocytes
10 μM
24 h
To investigate the effect of VX-765 on the thermogenic capacity of beige adipocytes, results showed that VX-765 treatment reduced the expression of UCP1, P-PKA, and P-HSL
Adv Sci (Weinh). 2024 Mar;11(10):e2303341.
BMDMs
20 µM
12 h
Inhibited non-canonical inflammasome activation
EMBO Mol Med. 2020 Jan 9;12(1):e9386.
HK2 cells
20 µg/ml
30 min
To inhibit caspase-1 and its related pyroptosis
Int J Biol Sci. 2023 Jan 1;19(2):593-609.
PC12 cells
50 μM
24 h
VX-765 pretreatment inhibited ketamine-induced pyroptosis in PC12 cells, reducing LDH release and levels of inflammatory cytokines (IL-1β and IL-18).
J Neuroinflammation. 2021 Oct 19;18(1):239.
HAPI cells
10 μM
24 h
VX-765 pretreatment significantly reduced ketamine-induced pyroptosis in HAPI cells, decreasing LDH release and levels of inflammatory cytokines (IL-1β and IL-18).
J Neuroinflammation. 2021 Oct 19;18(1):239.
VX-765 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Neonatal rats
Ketamine-induced neurotoxicity model
Intraperitoneal injection
25 mg/kg
Every 90 minutes, 5 doses
VX-765 pretreatment alleviated ketamine-induced hippocampal neuronal loss and improved cognitive dysfunction in neonatal rats.
J Neuroinflammation. 2021 Oct 19;18(1):239.
Mice
MC903-induced AD model
Oral
50 mg/kg
Once daily for 7 days
To evaluate the effect of VX-765 on IL-33 expression and secretion in the MC903-induced AD model, results showed that VX-765 had no significant effect on IL-33 secretion
Cell Death Dis. 2021 Sep 24;12(10):871
Mice
HFD-induced obesity model
Intraperitoneal injection
5 mg/kg
Every other day for 2 weeks
To investigate the effect of VX-765 on HFD-induced obese mice, results showed that VX-765 treatment alleviated obesity and metabolic disorders
Adv Sci (Weinh). 2024 Mar;11(10):e2303341.
Mice
DSS-induced colitis model
Intraperitoneal injection
20 mg/kg
Once daily for 6 days
VX-765 significantly reduced mortality, loss, and clinical scores in mice with colitis, and decreased the production of inflammatory cytokines IL-1β and IL-6 in colonic tissues.
EMBO Mol Med. 2020 Jan 9;12(1):e9386.
Mice
70% partial hepatectomy model
Oral
100 mg/kg
Single dose, 4 hours before surgery
To investigate the effect of VX-765 on liver regeneration, results showed that VX-765 had no effect on the cleavage of GSDMD
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