VX-765 is a novel and irreversible IL-converting enzyme/caspase-1 inhibitor with an IC50 of 0.8 nM. VRT-043198, a potent and selective inhibitor of ICE/caspase-1 sub-family caspases is an active metabolite VX-765. VRT-043198 exhibits 100-10,000-fold selectivity against other caspase-3 and -6-9. VX-765 was efficiently converted to VRT-043198 when administered orally to mice and inhibited LPS-induced cytokine secretion. VX-765 has been shown to inhibit acute partial seizures in preclinical models and has shown activity in preclinical models of chronic partial epilepsy that do not respond to currently available medicines for epilepsy. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation.
Free Radic Biol Med. 2023 Mar 27;202:46-61.
Mitochondrial GRIM-19 loss in parietal cells promotes spasmolytic polypeptide-expressing metaplasia through NLR family pyrin domain-containing 3 (NLRP3)-mediated IL-33 activation via a reactive oxygen species (ROS) -NRF2- Heme oxygenase-1(HO-1)–NF–кB axis
VX-765 (Belnacasan) purchased from AbMole
Arch Oral Biol. 2023 Feb 8;148:105642.
N-acetylcysteine protects human periodontal ligament fibroblasts from pyroptosis and osteogenic differentiation dysfunction through the SIRT1/NF-κB/Caspase-1 signaling pathway
VX-765 (Belnacasan) purchased from AbMole
Front Oncol. 2021 Sep 24;11:728047.
Antidiabetic DPP-4 Inhibitors Reprogram Tumor Microenvironment That Facilitates Murine Breast Cancer Metastasis Through Interaction With Cancer Cells via a ROS–NF-кB–NLRP3 Axis
VX-765 (Belnacasan) purchased from AbMole
EMBO Mol Med. 2020 Jan 9;12(1):e9386.
Glutathione peroxidase 8 negatively regulates caspase-4/11 to protect against colitis.
VX-765 (Belnacasan) purchased from AbMole
Cell Experiment | |
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Cell lines | human PBMCs |
Preparation method | A total of 2×105 cells/well (100 μL cell suspension) is distributed in triplicate in flat-bottom 96-well plates. Either 50 μL of Belnacasan (40 μM in RPMI 1640 complete medium containing 0.2% DMSO) or vehicle control is added to appropriate wells. Following a 30-min incubation at 37°C, 50 μL of LPS diluted in RPMI 1640 complete medium is added at final concentrations varying from 0.001 to 10 ng/mL. Cells are returned to a 37°C incubator. At 4 h after LPS addition, 75 μL of supernatant is removed from wells, cleared by centrifugation for 5 min at 1500 rpm, and stored at 4°C until assayed. Cells are returned to a 37°C incubator until 24 h after LPS addition, at which time 100 μL of supernatant is removed, cleared by centrifugation, and stored at 4°C. Supernatants are tested using ELISA kits for IL-1β, IL-6, IL-18, and IL-1α. |
Concentrations | 40 μM |
Incubation time | 4 h, 24 h |
Animal Experiment | |
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Animal models | Collagen-Induced Arthritis Model in Mouse |
Formulation | 25% Cremophor EL |
Dosages | 10-100 mg/kg twice daily |
Administration | oral gavage |
Molecular Weight | 509 |
Formula | C24H33ClN4O6 |
CAS Number | 273404-37-8 |
Solubility (25°C) | DMSO 90 mg/mL |
Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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Trimethylamine N-oxide dihydrate is a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients.Trimethylamine N-oxide dihydrate induces inflammation by activating ROS/NLRP3 inflammasome, and also accelerates fibroblast differentiation and induces cardiac fibrosis by activating TGF-β/smad2 signaling pathway. In addition, Trimethylamine N-oxide dihydrate induces tumor cell pyroptosis and enhances CD8+ T cell-mediated antitumor responses in triple-negative breast cancer. |
Sodium metatungstate
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LDC7559
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CY-09
CY-09 is a selective direct inhibitor of NLRP3 with anti-inflammatory and antidepressant activity, which inhibits inflammatory cytokine production and TRPA1 activation by inhibiting the activation of the NLRP3 inflammatory vesicle, thereby decreasing the intracellular Ca2+ level and reducing the pro-inflammatory polarization of macrophages, alleviating pain and injury in animals. In addition, CY-09 can inhibit pyroptosis. |
MCC950 sodium salt (CP-456773)
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