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| Targets |
The primary targets of Emidurdar include volume-regulated anion channels (VRAC/VSOAC), Anoctamin-1 (ANO1/TMEM16A) chloride channels, SRPK1, and ABCG2. It acts as a potent VRAC blocker with an IC50 of 460 nM and inhibits red blood cell chloride conductance with an IC50 of 0.6 μM. Emidurdar is also an ANO1 inhibitor. Upon oral administration, Emidurdar targets, binds to and inhibits the activity of SRPK1 and ABCG2. Inhibition of the cellular efflux pump ABCG2 by Emidurdar prevents the efflux of co-administered chemotherapeutic agents from cancer cells, potentially enhancing their efficacy. Emidurdar reduces TNFα-induced apoptosis and increases p53 protein levels and downstream signaling.
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| ln Vitro |
Endovion (NS3728, 10-100 μM) inhibits TNFα-induced apoptosis and raises p53 protein levels and downstream signaling, activating Caspase-9/-3 in cisplatin-sensitive cells and p21Waf1/Cip1, Bax, Noxa, and MDM2. Capan-1, AsPC-1, and BxPC-3 cell proliferation is inhibited by endovion (NS3728, 10 μM) [2].
In vitro, Emidurdar is a potent VRAC blocker with an IC50 of 460 nM and inhibits red blood cell chloride conductance with an IC50 of 0.6 μM. It is also an ANO1 inhibitor. Emidurdar (10-100 μM) reduces TNFα-induced apoptosis and increases p53 protein levels as well as downstream signaling, such as p21Waf1/Cip1. The compound's activity is typically measured using patch-clamp electrophysiology in cells expressing VRAC or ANO1 channels, or using chloride flux assays in red blood cells. These assays confirm that Emidurdar engages its targets and produces the expected effects on anion channel activity and chloride conductance. |
| ln Vivo |
In vivo, Emidurdar is an orally available anion channel inhibitor that has been studied for its potential to enhance the efficacy of chemotherapeutic agents by inhibiting ABCG2-mediated drug efflux. By inhibiting the cellular efflux pump ABCG2, Emidurdar prevents the efflux of co-administered chemotherapeutic agents from cancer cells, potentially increasing their intracellular concentrations and enhancing their anticancer activity. The compound's ability to reduce TNFα-induced apoptosis and increase p53 signaling may also contribute to its therapeutic effects. While specific in vivo efficacy data for Emidurdar are not extensively detailed in the available literature, its mechanism of action suggests that it could be a valuable adjunct to chemotherapy.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for Emidurdar are not conventional enzyme inhibition studies, as the compound is an ion channel blocker rather than an enzyme inhibitor. Instead, the primary assays involve electrophysiological recordings using patch-clamp techniques in cells expressing VRAC, ANO1, or other anion channels. In these assays, Emidurdar is applied to cells, and the amplitude of anion currents is measured. The IC50 for VRAC blockade (460 nM) and red blood cell chloride conductance inhibition (0.6 μM) are determined from dose-response curves. Radioligand binding studies or surface plasmon resonance (SPR) can be employed to measure the compound's affinity for ABCG2 and SRPK1.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: wild-type, resistant, and transiently transfected A2780 cells. Tested Concentrations: 10-100 μM. Incubation Duration: 18 or 4.5 hrs (hours). Experimental Results: The maximum taurine rate constant was diminished by more than 90% compared to untreated control cells. Resulting in increased LRRC8A protein expression. p53 and p21Waf1/Cip1 protein levels were Dramatically diminished in A2780WT cells. Cell proliferation assay[2] Cell Types: Capan-1, AsPC-1, BxPC-3 and H6c7 cell lines. Tested Concentrations: 10μM. Incubation Duration: 24 hrs (hours). Experimental Results: +67 mV produced the most significant inhibition of all cell lines, with 77 ± 26 % for Capan-1, 67 ± 9 % for AsPC-1, and 54 ± 8 % for BxPC-3 cells. In vitro cellular assays for Emidurdar are conducted in cells expressing VRAC, ANO1, or other anion channels, or in cancer cell lines for studies of drug efflux and apoptosis. Cells are treated with varying concentrations of Emidurdar, and anion channel activity is assessed using electrophysiological recordings or chloride flux assays. The compound's effects on ABCG2-mediated drug efflux are assessed by measuring the intracellular accumulation of a fluorescent ABCG2 substrate. Apoptosis is evaluated by measuring caspase activation, annexin V staining, or p53 and p21 levels. These assays confirm that Emidurdar engages its targets in a cellular context and produces the expected effects on anion channel activity, drug efflux, and apoptosis. |
| Animal Protocol |
In vivo animal studies for Emidurdar would typically be conducted in mouse xenograft models using cancer cell lines. Animals would be administered Emidurdar alone or in combination with a chemotherapeutic agent, and tumor growth inhibition would be monitored. The compound's effects on ABCG2-mediated drug efflux in tumors could be assessed by measuring the intracellular accumulation of a fluorescent ABCG2 substrate or by analyzing drug levels in tumor tissue. Pharmacokinetic studies would be performed to determine the compound's oral bioavailability, half-life, and tissue distribution.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Emidurdar indicate that it has a molecular weight of 495.18 and a molecular formula of C16H9BrF6N6O. The compound is orally available, enabling convenient administration for in vivo studies. It is soluble in DMSO, facilitating its use in in vitro assays and formulation for in vivo administration. For storage, the powder should be kept under appropriate conditions to maintain stability. The compound's purity is typically high, ensuring quality and reproducibility in experimental studies.
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| Toxicity/Toxicokinetics |
The toxicological profile of Emidurdar is primarily derived from its use as a research compound in preclinical studies. As an anion channel inhibitor, potential on-target effects could include changes in cell volume regulation, proliferation, and apoptosis, given the roles of VRAC and ANO1 in these processes. The compound's inhibition of ABCG2 could also affect the disposition of endogenous substrates and increase the toxicity of co-administered drugs. Comprehensive toxicology studies would be required for therapeutic development, including assessments of renal, hepatic, and hematopoietic function.
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| References |
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| Additional Infomation |
See also: NS-3728 (Notes have been moved).
Emidurdar (Endovion; NS-3728) is a pharmacological anion channel inhibitor that blocks VRAC/VSOAC and inhibits ANO1 chloride channels. It has an IC50 of 460 nM for VRAC blockade and an IC50 of 0.6 μM for red blood cell chloride conductance inhibition. Emidurdar targets SRPK1 and ABCG2, inhibiting the cellular efflux pump ABCG2. The compound reduces TNFα-induced apoptosis and increases p53 and p21 signaling. It is not approved for clinical use and is available from research chemical suppliers for preclinical studies. |
| Molecular Formula |
C16H9BRF6N6O
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|---|---|
| Molecular Weight |
495.18
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| Exact Mass |
493.993
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| CAS # |
265646-85-3
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| PubChem CID |
10005966
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| Appearance |
White to off-white solid powder
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| LogP |
5.397
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
30
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| Complexity |
586
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
AEFYFGMSRKDXHZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H9BrF6N6O/c17-9-1-2-12(11(6-9)13-26-28-29-27-13)25-14(30)24-10-4-7(15(18,19)20)3-8(5-10)16(21,22)23/h1-6H,(H2,24,25,30)(H,26,27,28,29)
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| Chemical Name |
1-[3,5-bis(trifluoromethyl)phenyl]-3-[4-bromo-2-(2H-tetrazol-5-yl)phenyl]urea
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| Synonyms |
NS-3728; NS 3728; NS3728
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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 (~252.43 mM)
H2O : < 0.1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.20 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 20.8 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: ≥ 2.08 mg/mL (4.20 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0195 mL | 10.0973 mL | 20.1947 mL | |
| 5 mM | 0.4039 mL | 2.0195 mL | 4.0389 mL | |
| 10 mM | 0.2019 mL | 1.0097 mL | 2.0195 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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