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Purity: ≥98%
VBIT-4 is a novel and potent inhibitor of VDAC1 (voltage-dependent anion channel 1), which is the outer mitochondrial membrane protein and a convergence point for a variety of cell survival and death signals, including apoptosis. VBIT-4 decreases mtDNA release, IFN signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus. The interaction of VBIT-4 with recombinant purified VDAC1, VDAC2, and VDAC3 was analyzed using the MST method. VBIT-4 bound to the three recombinant isoforms with a similar binding affinity, although 3-fold lower than that of VDAC1 purified from rat liver mitochondria. VDAC1 is the major isoform in most cell types, and no VDAC2 or VDAC3 oligomerization has been reported, it is reasonable to assume that the anti-apoptotic effect of VBIT-4 is mainly mediated via its interaction with VDAC1. VBIT-4 offers a therapeutic strategy for treating different diseases associated with enhanced apoptosis and point to VDAC1 as a promising target for therapeutic intervention.
| Targets |
VDAC, mtDNA release, IFN signaling, neutrophil extracellular traps
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| ln Vitro |
The interaction of VBIT-4 with recombinant purified VDAC1, VDAC2, and VDAC3 was analyzed using the MST method. VBIT-4 bound to the three recombinant isoforms with a similar binding affinity, although 3-fold lower than that of VDAC1 purified from rat liver mitochondria.[1]
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| ln Vivo |
The VDAC oligomerization inhibitor VBIT-4 decreases mtDNA release, IFN signaling, neutrophil extracellular traps, and disease severity in a mouse model of systemic lupus erythematosus. Thus, VDAC oligomerization inhibition is a potential therapeutic approach for diseases associated with mtDNA release.
VBIT-4 could ameliorate lupus-like symptoms in MpJ-Faslpr mice. VBIT-4 blocked the development of skin lesions and the thickening of the epidermis that accompanies leukocyte infiltration, and suppressed facial and dorsal alopecia without affecting mortality or body weight. VBIT-4 also decreased spleen and lymph node weights. [2] |
| Enzyme Assay |
High-throughput Screening to Identify Inhibitors of VDAC1 Oligomerization The screen was conducted using the cells in a 96-well format for enhancement of BRET2 signals to identify inhibitors of VDAC1 oligomerization. T-REx cells with low VDAC1 levels were transfected to express rVDAC1-GFP2 and rVDAC1-Rluc and seeded at a density of 9,000 cells/well in a 96-well plate. Compounds (1 μl of 2 mm stock solutions) were added to a final concentration of 10 μm in 100 μl (1% final DMSO concentration). The cells were pre-incubated for 1 h with the NCI compounds and then incubated with the apoptosis inducers for an additional 3 h (STS, 1 μm; selenite, 30 μm; As2O3, 60 μm). The tested NCI compounds were dispensed by a robotic system into the 96-well plates. After treatment, the medium was removed and assayed for BRET2 signals as described above. Liquid handling was done with the Tecan (Männedorf, Switzerland) Freedom 150 Robotic & MCA Liquid Handling System, although luciferase luminescence and fluorescence readings were obtained a robot-integrated Tecan Infinite M1000 reader.[1]
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| Cell Assay |
Cross-linking Experiments Cells (2.5–3 mg/ml) in PBS were harvested after the appropriate treatment and incubated with the cross-linking reagent EGS, pH 8.3, for 15 min. Samples (60–80 μg of protein) were subjected to SDS-PAGE and immunoblotting using anti-VDAC1 antibodies. Quantitative analysis of immunoreactive VDAC1 dimer, trimer, and multimer bands was performed using FUSION-FX. [1]
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| Animal Protocol |
Animal model of SLE (systemic lupus erythematosus)
Formulation: VBIT-4 was freshly dissolved in DMSO and diluted in water (final pH 5.0, DMSO 0.05%). Doses: 20 mg/kg Administration route: taken with drinking water Animal model of SLE (systemic lupus erythematosus). All experiments were approved by the ACUC (Animal Care and Use Committee) of the NIH/NHLBI. Female MRL/MpJ-Faslpr/J mice (stock #000485) were used as a model to determine the etiology of systemic lupus erythematosus (SLE). MRL/MpJ mice were used as a control for MRL/MpJ-Faslpr/J mice. All mice were purchased from The Jackson Laboratory. VBIT-4 was freshly dissolved in DMSO and diluted in water (final pH 5.0, DMSO 0.05%). The MRL/MpJ-Faslpr/J mice were treated with a daily freshly diluted dose of VBIT-4 (20 mg/kg) or vehicle water (final pH 5.0, DMSO 0.05%) in drinking water for 5 w, beginning at 11 w of age until euthanasia at 16 w of age. Blood and urine samples were collected when the mice were 16 w of age. Body weight were measured before and after VBIT-4 administration (11 and 16 w of age respectively). Skin, kidney, thymus, and lymph nodes were also collected.[2] |
| References |
[1] Novel Compounds Targeting the Mitochondrial Protein VDAC1 Inhibit Apoptosis and Protect against Mitochondrial Dysfunction. J Biol Chem. 2016 Nov 25;291(48):24986-25003. doi: 10.1074/jbc.M116.744284. Epub 2016 Oct 13.\nPMID: 27738100; [2] Science. 2019 Dec 20;366(6472):1531-1536. doi: 10.1126/science.aav4011. Epub 2019 Dec 19.\nPMID: 31857488 [3] Sci Rep. 2020 Dec 16;10(1):22101. doi: 10.1038/s41598-020-79056-w.PMID: 33328613 |
| Molecular Formula |
C21H23CLF3N3O3
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|---|---|
| Molecular Weight |
457.8738
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| Exact Mass |
457.138Molecular Weight
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| Elemental Analysis |
C, 55.09; H, 5.06; Cl, 7.74; F, 12.45; N, 9.18; O, 10.48
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| CAS # |
2086257-77-2
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| Related CAS # |
2086257-77-2 (racemate);2086268-69-9 (R-isoemr);2086269-51-2 (S-isomer);
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| Appearance |
Solid powder
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| LogP |
3.9
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| tPSA |
65Ų
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| SMILES |
OCC(N1CCN(C2=CC=C(OC(F)(F)F)C=C2)CC1)CC(NC3=CC=C(Cl)C=C3)=O
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| InChi Key |
QYSQXVAEFPWMEM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H23ClF3N3O3/c22-15-1-3-16(4-2-15)26-20(30)13-18(14-29)28-11-9-27(10-12-28)17-5-7-19(8-6-17)31-21(23,24)25/h1-8,18,29H,9-14H2,(H,26,30)
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| Chemical Name |
N-(4-chlorophenyl)-4-hydroxy-3-(4-(4-(trifluoromethoxy)phenyl)piperazin-1-yl)butanamide
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| Synonyms |
VBIT-4; VBIT4; VBIT 4
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : 90 mg/mL (~200 mM)
Ethanol : 40-90 mg/mL Water : < 1 mg/mL (Insoluble) |
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| Solubility (In Vivo) |
~4.5 mg/ml (9.8 mM) in 5% DMSO: 40% PEG300: 5% Tween 80: 50% ddH2O (Please use freshly prepared in vivo formulations for optimal results.)
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1840 mL | 10.9201 mL | 21.8403 mL | |
| 5 mM | 0.4368 mL | 2.1840 mL | 4.3681 mL | |
| 10 mM | 0.2184 mL | 1.0920 mL | 2.1840 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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