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| 5mg |
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| 10mg |
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| Targets |
WNK-IN-11 targets the With-No-Lysine (WNK) family of serine/threonine kinases, specifically WNK1. It is an allosteric inhibitor, meaning it binds to a site other than the ATP-binding pocket, which contributes to its high selectivity. By inhibiting WNK1, WNK-IN-11 blocks the phosphorylation and activation of downstream kinases SPAK and OSR1. This, in turn, reduces the phosphorylation of ion cotransporters such as NKCC2 and NCC, leading to decreased sodium reabsorption and blood pressure lowering effects.
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| ln Vitro |
In the cellular OSR1 phosphorylation experiment, WNK-IN-11 (Compound 11) exhibits IC50<2 μM and has a respectable water solubility, but microsomal clearance is still rather high. WNK-IN-11 exhibits ATP inhibition that is noncompetitive. WNK-IN-11 demonstrated remarkable selectivity when tested against a panel of 440 human kinases at a concentration of 10 μM (2500-fold higher than the enzyme IC50 value), with only a few notable off-target kinase inhibitions. Notably, BTK and feline encephalitis virus-related inhibitory (FER) kinase, neither of which is involved in blood pressure regulation, are of interest. This highly conserved projected allosteric binding mechanism outside the ATP pocket is consistent with this outstanding selectivity profile [1].
WNK-IN-11 is a potent inhibitor of WNK1 with an IC50 of 4 nM in cell-free assays. It shows an IC50 of <2 μM in the cellular OSR1 phosphorylation assay, demonstrating its activity in a cellular context. The compound has reasonable aqueous solubility. It is highly selective for WNK1 over other kinases, making it a valuable tool for studying WNK signaling. |
| ln Vivo |
WNK-IN-11 has shown in vivo efficacy in preclinical models. As an orally active compound, it is suitable for oral administration in animal studies. It has been shown to modulate blood pressure in animal models, consistent with its mechanism of action. The compound's ability to inhibit WNK1 and downstream signaling pathways makes it a promising candidate for the treatment of hypertension and related disorders.
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| Enzyme Assay |
The in vitro kinase assay for WNK-IN-11 typically involves measuring the kinase activity of recombinant WNK1 using a radioactive or fluorescence-based assay. The compound is incubated with the enzyme, a peptide substrate, and ATP, and the phosphorylation level is quantified to determine the IC50. Selectivity is assessed by testing the compound against a panel of other kinases.
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| Cell Assay |
The in vitro cellular assay for WNK-IN-11 typically involves culturing cells that express WNK1 and its downstream targets. Cells are treated with varying concentrations of the compound, and the phosphorylation of OSR1 is measured by Western blotting using phospho-specific antibodies. The IC50 for inhibition of OSR1 phosphorylation is determined from the dose-response curve.
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| Animal Protocol |
In vivo animal studies for WNK-IN-11 typically involve the use of rodent models of hypertension. Animals are administered the compound via oral gavage at various doses. Blood pressure is measured using telemetry or tail-cuff methods. The compound's effects on electrolyte balance and renal function are also assessed.
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| ADME/Pharmacokinetics |
WNK-IN-11 has a molecular weight of 462.40 g/mol and a molecular formula of C21H21Cl2N5OS. The compound has a purity of 99.87%. It is soluble in DMSO (92 mg/mL, 198.96 mM) and ethanol (32 mg/mL), but insoluble in water. For oral administration, it can be formulated as a homogeneous suspension in CMC-Na (≥5 mg/mL). Further detailed PK parameters are available from the manufacturer's data sheets.
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| Toxicity/Toxicokinetics |
Specific toxicology data for WNK-IN-11 are not available in the public domain. The compound is intended for research use only and should be handled with appropriate laboratory safety precautions. Standard safety assessments would be required before any clinical application. Researchers should consult the safety data sheet for detailed handling and disposal information.
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| References | |
| Additional Infomation |
WNK-IN-11 is a potent, selective, and orally active allosteric inhibitor of With-No-Lysine (WNK) kinases. It has an IC50 of 4 nM for WNK1. The compound suppresses downstream SPAK/OSR1 signaling and modulates ion transport. It is a valuable research tool for investigating WNK signaling pathways in hypertension and renal physiology. It has not yet entered clinical trials and is strictly for preclinical research purposes.
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| Molecular Formula |
C21H21CL2N5OS
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|---|---|
| Molecular Weight |
462.395340681076
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| Exact Mass |
461.084
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| CAS # |
2123489-30-3
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| Related CAS # |
WNK-IN-11-d3;2123483-49-6
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| PubChem CID |
133080583
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| Appearance |
White to off-white solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
572
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CN=C(C2=CSC(NC)=N2)C=C1C(N1CCN(CC2C=CC(=CC=2)Cl)CC1)=O
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| InChi Key |
MVXAYIXYYOVALX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H21Cl2N5OS/c1-24-21-26-19(13-30-21)18-10-16(17(23)11-25-18)20(29)28-8-6-27(7-9-28)12-14-2-4-15(22)5-3-14/h2-5,10-11,13H,6-9,12H2,1H3,(H,24,26)
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| Chemical Name |
[5-chloro-2-[2-(methylamino)-1,3-thiazol-4-yl]pyridin-4-yl]-[4-[(4-chlorophenyl)methyl]piperazin-1-yl]methanone
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| Synonyms |
WNKIN11; WNK IN 11; WNK-IN-11
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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 : ~150 mg/mL (~324.39 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.41 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 25.0 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: ≥ 2.5 mg/mL (5.41 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 25.0 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 | 2.1626 mL | 10.8131 mL | 21.6263 mL | |
| 5 mM | 0.4325 mL | 2.1626 mL | 4.3253 mL | |
| 10 mM | 0.2163 mL | 1.0813 mL | 2.1626 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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