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| Targets |
WS-898 specifically targets ABCB1 (P-glycoprotein, P-gp), a member of the ATP-binding cassette (ABC) transporter family. ABCB1 is an ATP-dependent efflux pump that exports a wide range of xenobiotics, including many chemotherapeutic agents (e.g., paclitaxel, doxorubicin, vinca alkaloids), out of cancer cells. WS-898 acts as an ABCB1 inhibitor, which means it binds to the transporter and blocks its efflux function, leading to the intracellular accumulation of chemotherapeutic drugs.
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| ln Vitro |
In vitro, WS-898 is a highly effective ABCB1 inhibitor. It demonstrates potent activity in reversing paclitaxel (PTX) resistance in various drug-resistant cell lines, with IC50 values of 5.0 nM, 3.67 nM, and 3.68 nM in SW620/Ad300 (colon cancer), KB-C2 (cervical carcinoma), and HEK293/ABCB1 (HEK293 cells overexpressing ABCB1) cells, respectively.. These low nanomolar IC50 values indicate that WS-898 is a very potent chemosensitizer, capable of restoring sensitivity to paclitaxel at extremely low concentrations.
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| ln Vivo |
Specific in vivo activity data for WS-898 has not been detailed in the provided search results. As a potent ABCB1 inhibitor, it is hypothesized to enhance the anti-tumor activity of paclitaxel in vivo. Using a mouse xenograft model of a multidrug-resistant human cancer (e.g., SW620/Ad300 colon carcinoma), the combination of WS-898 (a low, non-toxic dose) with paclitaxel would be expected to result in significantly greater tumor regression compared to paclitaxel alone, without increasing systemic toxicity. This would confirm its ability to reverse P-gp-mediated drug resistance in living animals.
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| Enzyme Assay |
The standard in vitro protocol for assessing ABCB1 inhibition is a calcein-AM accumulation assay using cells that overexpress ABCB1. SW620/Ad300 cells (or KB-C2 cells) are seeded in 96-well black-walled plates. The cells are pre-incubated with varying concentrations of WS-898 (0.01-100 nM) for 30 minutes at 37degC. Then, 0.5 uM calcein-AM (a fluorescent substrate for ABCB1) is added to each well and incubated for 30 minutes. ABCB1 actively pumps calcein-AM out of the cells; therefore, in the absence of an inhibitor, the cells remain non-fluorescent. Upon inhibition of ABCB1, calcein-AM accumulates in the cells and is cleaved by intracellular esterases to produce calcein (a highly fluorescent molecule). The fluorescence signal (Ex/Em = 485/535 nm) is measured using a microplate reader. The IC50 is calculated from the fluorescence increase, and the values (3.67-5.0 nM) are determined.
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| Cell Assay |
The in vitro cellular assay for WS-898 uses a standard chemosensitivity assay (MTT or CellTiter-Glo) in drug-resistant cancer cell lines. SW620/Ad300 cells (resistant to paclitaxel) are seeded in 96-well plates at 5×103 cells/well. A fixed concentration of WS-898 (e.g., 5-10 nM, based on its IC50) is added to all wells. Then, a serial dilution of paclitaxel (0.1-1000 nM) is added to the cells. The cells are incubated for 72 hours. After incubation, cell viability is measured using a standard MTT assay or CellTiter-Glo reagent. The ability of WS-898 to reverse resistance is determined by the reduction in the IC50 of paclitaxel. In the presence of WS-898, the IC50 of paclitaxel in the resistant cells should shift to a value comparable to that in the parental (sensitive) cells.
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| Animal Protocol |
An in vivo protocol for WS-898 would involve a subcutaneous xenograft model using a multidrug-resistant human cancer cell line. Female athymic nude mice (6-8 weeks) are inoculated subcutaneously with SW620/Ad300 colon cancer cells. When tumors reach an average volume of 150-200 mm3, mice are randomized into four groups: (1) Vehicle control, (2) Paclitaxel alone (10 mg/kg, IV, once every 3 days), (3) WS-898 alone (5 mg/kg, IP, daily), (4) WS-898 + paclitaxel (combination). WS-898 is formulated in a suitable vehicle (e.g., 5% DMSO/40% PEG300/5% Tween-80/50% ddH2O) and administered 1 hour prior to paclitaxel. Tumor volumes are measured twice weekly with calipers. The primary efficacy endpoint is tumor growth inhibition (TGI). The combination group should demonstrate a significantly slower tumor growth and a much higher tumor regression rate compared to paclitaxel alone, indicating that WS-898 successfully reversed P-gp-mediated resistance in vivo.
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| ADME/Pharmacokinetics |
Detailed pharmacokinetic (PK) data for WS-898 is not provided. A standard PK study in mice would involve oral (PO) administration (10 mg/kg) and intravenous (IV) administration (1 mg/kg). Blood samples are collected at multiple time points (0-24 h), and plasma concentrations of WS-898 are quantified by LC-MS/MS. Key parameters, including terminal half-life (T1/2), maximum plasma concentration (Cmax), area under the curve (AUC), and oral bioavailability (F%), would be calculated. The compound is likely metabolized by the liver, possibly by CYP3A4. For research, it is typically dissolved in DMSO for in vitro studies.
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| Toxicity/Toxicokinetics |
Specific toxicological data for WS-898 is not available. As an ABCB1 inhibitor, the primary safety concern is the potential for increased toxicity of co-administered chemotherapeutic agents (e.g., paclitaxel, doxorubicin) due to their enhanced accumulation in normal tissues, particularly the bone marrow and gastrointestinal tract. This could lead to severe myelosuppression, neurotoxicity, and mucositis. Standard safety assessment would involve a 14-day repeat-dose combination toxicity study in rats (e.g., WS-898 + paclitaxel) to determine the Maximum Tolerated Dose (MTD) and to evaluate if the combination exacerbates the toxicity of paclitaxel alone. Blood counts (CBC) and histopathology of the bone marrow, gut, and peripheral nerves would be critical endpoints.
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| References | |
| Additional Infomation |
WS-898 is a research-grade chemical and is not approved for clinical use. It is a highly potent ABCB1/P-glycoprotein inhibitor (IC50s in the low nanomolar range: 5.0 nM, 3.67 nM, and 3.68 nM).. It is designed to overcome multidrug resistance (MDR) in cancer chemotherapy by blocking the efflux pump that exports drugs like paclitaxel from cancer cells. WS-898 is a valuable tool for studying the molecular pharmacology of P-gp and for the development of chemosensitizers that could be used in combination therapy for drug-resistant cancers. It is for research use only.
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| Molecular Formula |
C33H25N7OS
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| Molecular Weight |
567.662904500961
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| Exact Mass |
567.184
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| CAS # |
2891562-77-7
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| PubChem CID |
162366971
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| Appearance |
White to light yellow solid powder
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| LogP |
7.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
42
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| Complexity |
943
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=NC2=NC(=NN2C(=C1)NC3=CC=C(C=C3)C(=O)/C=C/C4=CC5=CC=CC=C5C=C4)SCC6=NC7=CC=CC=C7N6
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| InChi Key |
WGQWRCAZEPAXRA-GZTJUZNOSA-N
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| InChi Code |
InChI=1S/C33H25N7OS/c1-21-18-31(40-32(34-21)38-33(39-40)42-20-30-36-27-8-4-5-9-28(27)37-30)35-26-15-13-24(14-16-26)29(41)17-11-22-10-12-23-6-2-3-7-25(23)19-22/h2-19,35H,20H2,1H3,(H,36,37)/b17-11+
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| Chemical Name |
(E)-1-[4-[[2-(1H-benzimidazol-2-ylmethylsulfanyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]amino]phenyl]-3-naphthalen-2-ylprop-2-en-1-one
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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: ≥ 25 mg/mL (44.04 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 | 1.7616 mL | 8.8081 mL | 17.6162 mL | |
| 5 mM | 0.3523 mL | 1.7616 mL | 3.5232 mL | |
| 10 mM | 0.1762 mL | 0.8808 mL | 1.7616 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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