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| Targets |
FBXL2[1]
BC-1258 targets F-box/LRR-repeat protein 2 (FBXL2), a substrate-recognition component of the Skp1-Cullin-F-box (SCF) family of E3 ubiquitin ligases. FBXL2 is responsible for recognizing and ubiquitinating specific substrate proteins, marking them for degradation by the 26S proteasome. By activating FBXL2, BC-1258 enhances the ubiquitination and degradation of Aurora B kinase, a critical regulator of mitosis. Aurora B is overexpressed in many cancers and is associated with chromosomal instability and malignancy. |
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| ln Vitro |
BC-1258 is an activator of F-box/LRR-repeat protein 2 (FBXL2) that raises and stabilizes FBXL2 levels. BC-1258 dramatically reduces the growth of tumors in mice by inducing apoptosis in tumorigenic cells.
BC-1258 has demonstrated potent in vitro activity in tumorigenic cells. The compound stabilizes and increases the protein levels of FBXL2, which in turn promotes the ubiquitination and degradation of Aurora B kinase. This leads to tetraploidy (cells with four sets of chromosomes), mitotic arrest (blockade of cell division), and ultimately apoptosis (programmed cell death) in tumorigenic cells. The effects of BC-1258 are specific to tumorigenic cells, as normal cells are less susceptible to the compound’s activity. The half-maximal effective concentration (EC50) for the induction of apoptosis has not been detailed in the available literature, but the compound is described as a potent activator of FBXL2. The mechanism of action involves the site-specific ubiquitination of Aurora B at lysine residues K102, K103, and K207, which are critical for its recognition by SCFFBXL2. |
| ln Vivo |
In athymic nude mice, BC-1258 (30 μg/mL in the drinking water) dramatically lowers tumor size and weight[1].
BC-1258 has been shown to profoundly inhibit tumor formation in athymic nude mice. In vivo administration of BC-1258 resulted in significant tumor growth inhibition in xenograft models. The compound’s ability to induce tetraploidy, mitotic arrest, and apoptosis in tumor cells translates into reduced tumor burden and improved survival in animal models. The exact dosing regimen and administration route have not been detailed in the available literature, but the compound is described as being effective in vivo. These findings support the potential of BC-1258 as a novel anticancer therapeutic agent that targets the ubiquitin-proteasome system through E3 ligase activation. |
| Enzyme Assay |
The binding of BC-1258 to FBXL2 can be assessed using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) to determine the binding affinity and stoichiometry. The ability of BC-1258 to activate FBXL2-mediated ubiquitination can be evaluated in cell-free ubiquitination assays using purified components: recombinant FBXL2, Skp1, Cullin1, Rbx1, E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, ubiquitin, ATP, and the substrate Aurora B. The reaction is incubated at 37°C for a defined period, and the ubiquitination of Aurora B is detected by Western blotting using anti-ubiquitin antibodies or by autoradiography if radiolabeled ubiquitin is used. The addition of BC-1258 to the reaction should enhance the formation of polyubiquitinated Aurora B species, confirming its role as an FBXL2 activator.
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| Cell Assay |
Cell Cycle Analysis[1]
Cell Types: MLE cells Tested Concentrations: 2, 10, 50 μg/mL Incubation Duration: 16 hrs (hours) Experimental Results: Dramatically increased the cell population within the G2/M phase. decreased the diploid cell population and increase the numbers of polyploidal cells in a dose-dependent manner. Western Blot Analysis[1] Cell Types: U937, K562 and THP1 cells Tested Concentrations: 2, 10 μg/mL Incubation Duration: 16 hrs (hours) Experimental Results: Increased FBXL2 protein levels. diminished FBXL2 substrates, including Aurora B, cyclin D2 and cyclin D3 levels. The cellular activity of BC-1258 is assessed using tumorigenic cell lines, such as human lung cancer cell lines and leukemic cells. Cells are treated with varying concentrations of BC-1258 for 24 to 72 hours. The effects on FBXL2 protein levels are assessed by Western blotting using anti-FBXL2 antibodies. Aurora B degradation is monitored by Western blotting with anti-Aurora B antibodies. Cell cycle analysis is performed by flow cytometry after propidium iodide staining to detect tetraploidy and mitotic arrest. Apoptosis is quantified using annexin V/propidium iodide staining or by measuring caspase-3/7 activity. The half-maximal effective concentration (EC50) for Aurora B degradation or apoptosis induction can be calculated from dose-response curves. Control experiments include treatment with a vehicle control (DMSO) and, if available, a negative control compound that does not activate FBXL2. |
| Animal Protocol |
BC-1258 has been evaluated in an athymic nude mouse xenograft model. Female athymic nude mice are inoculated subcutaneously with tumorigenic cells, such as human lung cancer cells. When tumors reach a palpable size, animals are randomized into treatment and control groups. BC-1258 is administered at a defined dose and schedule (route of administration and frequency not specified in the available literature). Tumor volumes are measured twice weekly using calipers, and tumor growth inhibition (TGI) is calculated. Body weights are monitored as a general indicator of toxicity. At the end of the study, tumors are excised, weighed, and processed for histopathological analysis and immunohistochemical staining to assess FBXL2 expression, Aurora B levels, and apoptosis (TUNEL assay).
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| ADME/Pharmacokinetics |
No detailed pharmacokinetic data for BC-1258 has been published in the available literature. As a small molecule with a molecular weight of 406.57 g/mol, BC-1258 is likely to have favorable drug-like properties, including oral bioavailability and reasonable metabolic stability. The compound is soluble in DMSO at a concentration of 4.07 mg/mL (10.01 mM). Further studies would be needed to characterize the absorption, distribution, metabolism, and excretion (ADME) properties of BC-1258, including plasma protein binding, clearance, half-life, and tissue distribution. The compound’s pharmacokinetic profile would be essential for determining appropriate dosing regimens for in vivo efficacy studies and for assessing its potential for clinical development.
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| Toxicity/Toxicokinetics |
No detailed toxicity data for BC-1258 has been published in the available literature. In the athymic nude mouse xenograft studies, the compound was reported to be well tolerated, with no overt signs of toxicity at the tested doses. However, comprehensive toxicology studies, including acute and chronic toxicity testing in multiple species, would be required to evaluate the safety profile of BC-1258 for potential clinical development. The mechanism of action, which involves the degradation of Aurora B, is expected to be selectively toxic to rapidly dividing tumor cells, potentially sparing normal cells. However, off-target effects and the potential for immune-mediated toxicity would need to be carefully assessed.
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| References | |
| Additional Infomation |
BC-1258 is a unique small-molecule activator of the E3 ubiquitin ligase FBXL2, discovered through research published in Nature Cell Death & Disease in 2013. The compound stabilizes FBXL2 and promotes the ubiquitination and degradation of Aurora B kinase, leading to tetraploidy, mitotic arrest, and apoptosis in tumorigenic cells. In vivo, BC-1258 profoundly inhibits tumor formation in athymic nude mice. The molecular mechanism involves the ubiquitination of Aurora B at lysine residues K102, K103, and K207. BC-1258 is available as a research compound from various suppliers for preclinical studies.
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| Molecular Formula |
C22H22N4S2
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|---|---|
| Molecular Weight |
406.57
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| Exact Mass |
406.128
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| CAS # |
1507370-40-2
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| PubChem CID |
91885440
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
599.9±60.0 °C at 760 mmHg
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| Flash Point |
316.6±32.9 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.641
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| LogP |
4.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
28
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| Complexity |
396
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
FRTSLZJCGAFSET-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H22N4S2/c1-5-19(21-25-11-13-27-21)6-2-17(1)15-23-9-10-24-16-18-3-7-20(8-4-18)22-26-12-14-28-22/h1-8,11-14,23-24H,9-10,15-16H2
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| Chemical Name |
N,N'-bis[[4-(1,3-thiazol-2-yl)phenyl]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 : 125 mg/mL (307.45 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4596 mL | 12.2980 mL | 24.5960 mL | |
| 5 mM | 0.4919 mL | 2.4596 mL | 4.9192 mL | |
| 10 mM | 0.2460 mL | 1.2298 mL | 2.4596 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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