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BC-1215 is an inhibitor of F-box protein 3 (FBXO3, a ubiquitin E3 ligase component, IC50=0.9 μg/mL for IL-1β release). BC-1215 decreases Fbxo3-Fbxl2 interaction and prevents SCFFbxo3 catalyzed Fbxl2 ubiquitination. BC-1215 inhibits the Fbxo3-TRAF activation pathway by destabilizing TRAF1–TRAF6. BC-1215, interacts with ApaG to profoundly inhibit secretion of a broad spectrum of TH1 panel cytokines from human PBMC.
| Targets |
By destabilizing TRAF1-6, BC-1215 (0, 0.4, 2, 10, 50 μg/mL; 16 h, 18 h, and 24 h) inhibits the Fbxo3-TRAF activation pathway[1].
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| ln Vitro |
By destabilizing TRAF1-6, BC-1215 (0, 0.4, 2, 10, 50 μg/mL; 16 h, 18 h, and 24 h) inhibits the Fbxo3-TRAF activation pathway[1].
BC-1215 exhibited an IC50 of 0.9 μg/ml for inhibiting IL-1β release from LPS-stimulated human peripheral blood mononuclear cells (PBMC). The lethal concentration, 50% (LC50) was 87 μg/ml in U937 cells. [1] BC-1215 decreased the interaction between Fbxo3 and Fbxl2 in a dose-dependent manner and prevented SCFFbxo3-catalyzed ubiquitination of Fbxl2. [1] BC-1215 effectively reduced TRAF1-6 protein levels in U937 cells and primary human PBMCs under both resting conditions and after LPS stimulation. This reduction occurred without altering steady-state TRAF mRNA levels. [1] BC-1215 blunted the induction of TRAF1-6 proteins after ectopic expression of Fbxo3 plasmid in U937 cells. [1] BC-1215 inhibited LPS-induced secretion of a broad spectrum of cytokines (Th1 panel) in human PBMC. [1] |
| ln Vivo |
Induced inflammation caused by bacteria is lessened by BC-1215 (i.p.; 100 μg)[1].
In a murine cecal ligation and puncture (CLP)-induced sepsis model, administration of BC-1215 (100 μg, i.p.) significantly attenuated CLP-induced secretion of circulating IL-6, TNF, and IL-1β. [1] BC-1215 treatment decreased bacterial counts in the peritoneal fluid in the CLP model. [1] In a murine Pseudomonas aeruginosa (strain PA103) pneumonia model, administration of BC-1215 (100 μg, i.p.) significantly ameliorated adverse effects on lung mechanics, decreased bronchoalveolar lavage (BAL) protein concentration and cell counts, reduced lung cell infiltrates, and decreased BAL pro-inflammatory cytokine levels. [1] Similar beneficial effects of BC-1215 were observed in a murine H1N1 pneumonia model. [1] |
| Enzyme Assay |
Molecular docking studies were performed using Discovery Studio 3.1 software to screen a library of 6507 approved or experimental drugs for potential ligands of Fbxo3. Based on docking and best-fit analysis, benzathine was selected as a backbone to develop a series of new small molecules, including BC-1215. BC-1215 scored high on docking studies with the Fbxo3-ApaG domain. [1]
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| Cell Assay |
For cytokine release assays, human PBMC (0.6 ml at 1.5 × 106/ml) were treated with LPS (2 μg/ml) for 16 hours in the presence of varying concentrations of BC-1215. Cell-free medium was collected and assayed for cytokine (e.g., IL-1β) levels by ELISA to determine IC50 values. [1]
For cytotoxicity assessment, U937 cells (0.6 ml at 1.5 × 106/ml) were treated with BC-1215 for 16 hours. Cells were then stained with trypan blue to identify dead cells and calculate the LC50. [1] For protein analysis, U937 cells or PBMC were transfected or treated as indicated (e.g., with BC-1215 or LPS). Cells were harvested, lysed, and proteins were analyzed by immunoblotting for targets such as TRAFs, Fbxl2, and Fbxo3. [1] |
| Animal Protocol |
Animal Model: Sepsis model caused by cecal ligation and puncture (CLP)[1]
Dosage: 100 μg
Administration: i.p.
Result:reduced the number of bacteria in the CLP model and significantly attenuated the release of all three of the circulating pro-inflammatory cytokines when exposed to CLP.
For the CLP-induced sepsis model, mice were anesthetized and a midline laparotomy was performed. The cecum was exteriorized, ligated, and punctured with an 18-gauge needle. The abdomen was closed. Sham-operated animals received laparotomy only. BC-1215 (100 μg) or vehicle was administered via intraperitoneal (i.p.) injection immediately prior to the procedure. Mice were euthanized 6 hours later, and blood was collected for plasma cytokine analysis. Peritoneal fluid was obtained for bacterial counts. [1] For the P. aeruginosa pneumonia model, C57BL/6 mice were anesthetized, and the larynx was visualized for endotracheal intubation. P. aeruginosa (strain PA103, 104 CFU/mouse) was instilled intratracheally (i.t.). BC-1215 (100 μg) or vehicle was administered via i.p. injection immediately prior to bacterial challenge. Mice were euthanized 18 hours later. Lung mechanics were measured using a flexiVent system. Bronchoalveolar lavage (BAL) was performed with sterile PBS to collect fluid for protein, cell count, and cytokine analysis. Lung tissue was collected for histological examination (H&E staining). [1] For survival studies in the pneumonia model, mice were administered a higher dose of PA103 (105 CFU/mouse, i.t.) with or without BC-1215 treatment and monitored over time. [1] |
| Toxicity/Toxicokinetics |
In vitro experiments showed that the median lethal concentration (LC50) of BC-1215 against U937 cells was 87 μg/ml. This result was obtained 16 hours after treatment using the trypan blue exclusion method. [1]
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| References | |
| Additional Infomation |
BC-1215 is a small molecule inhibitor designed to target the Fbxo3 protein, which is a component of the SCF E3 ubiquitin ligase complex. It is based on a benzathine backbone and modified (e.g., by introducing a pyridine group) to optimize its interaction with the Fbxo3 ApaG domain. [1] The compound exerts its anti-inflammatory effect by antagonizing Fbxo3, which typically targets and degrades the inhibitory F-box protein Fbxl2. BC-1215 leads to increased ubiquitination and degradation of TRAF family proteins (TRAF1-6) by inhibiting Fbxo3 stabilization of Fbxl2. Decreased TRAF protein levels subsequently inhibit the production of downstream NF-κB signaling pathways and pro-inflammatory cytokines (e.g., TNF, IL-1β, IL-6). [1] This study suggests that the Fbxo3-TRAF pathway is associated with human sepsis, and that inhibitors like BC-1215 may have the potential to treat cytokine-driven inflammatory diseases. [1]
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| Molecular Formula |
C26H26N4
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|---|---|
| Molecular Weight |
394.51
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| Exact Mass |
394.215
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| CAS # |
1507370-20-8
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| PubChem CID |
72201045
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| Appearance |
White to off-white solid powder
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| Density |
1.1±0.1 g/cm3
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| Boiling Point |
589.9±50.0 °C at 760 mmHg
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| Flash Point |
310.6±30.1 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.613
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| LogP |
3.68
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
30
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| Complexity |
412
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
IXEPQJQQSLMESJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H26N4/c1-3-15-29-25(5-1)23-11-7-21(8-12-23)19-27-17-18-28-20-22-9-13-24(14-10-22)26-6-2-4-16-30-26/h1-16,27-28H,17-20H2
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| Chemical Name |
N,N'-bis[(4-pyridin-2-ylphenyl)methyl]ethane-1,2-diamine
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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 : 12.5~79 mg/mL ( 31.68~200.24 )
Ethanol : ~79 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (3.17 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.25 mg/mL (3.17 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.25 mg/mL (3.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5348 mL | 12.6739 mL | 25.3479 mL | |
| 5 mM | 0.5070 mL | 2.5348 mL | 5.0696 mL | |
| 10 mM | 0.2535 mL | 1.2674 mL | 2.5348 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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