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| Targets |
The target of VBY-825 is the family of cysteine cathepsin proteases, particularly Cathepsins B, L, S, and V. These enzymes are involved in a variety of physiological processes, including protein degradation, antigen presentation, and extracellular matrix remodeling. Overexpression and hyperactivation of cathepsins are implicated in various pathologies, including cancer progression (invasion and metastasis), inflammatory disorders, and bone diseases.
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| ln Vitro |
VBY-825 is a novel, reversible cathepsin inhibitor with high potency against cathepsins B, L, S and V. This isomer is the inactive control. In vitro, the active VBY-825 inhibits the proteolytic activity of cathepsins with IC50 values in the low nanomolar range (e.g., 2.3 nM for cathepsin S, 4.7 nM for cathepsin V, 130/250/330 nM for B/L/S). It also potently inhibits angiogenesis in tumor cell lines and tumor matrix invasion. The (S,R,R)-isomer shows negligible protease inhibition.
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| ln Vivo |
In vivo, the active VBY-825 demonstrates significant anti-tumor efficacy. In a preclinical mouse model of pancreatic islet cancer, VBY-825 significantly decreased tumor burden and tumor number. In a mouse model of bone cancer, it potently inhibited angiogenesis. The compound supported once-daily dosing, maintaining plasma levels sufficient for sustained target inhibition. The inactive isomer serves as a control, showing no anti-cancer activity.
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| Enzyme Assay |
The activity of the parent compound VBY-825 was determined via cell-free enzymatic assays using purified recombinant cathepsins. The assay involves incubating the enzyme (e.g., cathepsin B) with a fluorogenic peptide substrate (e.g., Z-FR-AMC) in assay buffer (e.g., 0.1 M sodium acetate, pH 5.5). Varying concentrations of the inhibitor are added, and the reaction is monitored for fluorescence (λ_ex 380 nm, λ_em 460 nm). The IC50 is calculated based on the reduction in fluorescence.
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| Cell Assay |
Cellular activity is evaluated using tumor cell lines (e.g., MDA-MB-231 breast cancer cells or endothelial cells). The compound is added to the culture media, and its effect is measured using co-culture assays to assess tumor matrix invasion or by Western blotting to analyze cathepsin processing. To confirm mechanism, cells are treated with the active inhibitor, and the reduction in specific substrate degradation is measured, while the inactive isomer serves as a negative control.
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| Animal Protocol |
The anti-tumor efficacy of the active compound was tested in a transgenic mouse model of pancreatic islet cancer (Rip1-Tag2 mouse). Mice were treated with VBY-825 (e.g., 10 mg/kg/day, oral or IP). Endpoints included terminal tumor burden (number and size of pancreatic islet tumors) and tumor invasion. A control group treated with (S,R,R)-VBY-825 is essential to demonstrate that the reduction in tumor burden is specifically due to cathepsin inhibition.
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| ADME/Pharmacokinetics |
The parent compound VBY-825 demonstrates favorable pharmacokinetic properties: it has good metabolic stability (93% remaining after 60 minutes in human liver microsomes), acceptable solubility (223 microM), and supports once-daily oral dosing. A 10 mg/kg/day dose achieves a trough plasma concentration >200 nM, sufficient for sustained inhibition of cathepsins intracellularly. The inactive isomer is not studied for PK but is expected to have similar absorption/distribution without target engagement.
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| Toxicity/Toxicokinetics |
The (S,R,R)-isomer itself is non-toxic at control concentrations. The active VBY-825 is well-tolerated in mouse models at therapeutic doses (10 mg/kg/day). Preclinical safety studies show a manageable safety profile. Potential target-mediated toxicities of cathepsin inhibitors may include bone growth abnormalities or immune modulation, but none were reported in these studies. The compound is for research use only.
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| References |
[1]. Elie BT, et al. Identification and pre-clinical testing of a reversible cathepsin protease inhibitor reveals anti-tumor efficacy in a pancreatic cancer model. Biochimie. 2010 Nov;92(11):1618-24.
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| Additional Infomation |
VBY-825 was discovered by Virobay Inc. via X-ray crystal structure-based drug design. It is a research-grade chemical tool. This active inhibitor has not progressed to FDA approval for cancer therapy but remains a valuable tool for studying the role of cathepsins in pancreatic cancer and other diseases. The (S,R,R)-isomer is the inactive control used in these discovery studies. This product is for research use only.
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| Molecular Formula |
C23H29F4N3O5S
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| Molecular Weight |
535.55
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| Related CAS # |
VBY-825;1310340-58-9
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| Appearance |
White to off-white solid powder
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 1.8672 mL | 9.3362 mL | 18.6724 mL | |
| 5 mM | 0.3734 mL | 1.8672 mL | 3.7345 mL | |
| 10 mM | 0.1867 mL | 0.9336 mL | 1.8672 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.
Products are for research use only; We do not sell to patients
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