WNK463
目录号 : GC19383
WNK463是一种口服WNK激酶抑制剂，对WNK1、WNK2、WNK3和WNK4的IC50值分别为5 nM、1 nM、6 nM和9 nM 。
Cas No.:2012607-27-9
Sample solution is provided at 25 µL, 10mM.
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WNK463 inhibits the pan-With-No-Lysine (K) (WNK) kinase, demonstrating IC50 values of 5 nM, 1 nM, 6 nM, and 9 nM for WNK1, WNK2, WNK3, and WNK4, respectively[1-2].
WNK463 at 1 μM for 15 minutes decreased KCC2 phosphorylation at site 1007 and increased KCC2 activity in HEK-293 cells[3]. WNK463(10 μM ;2h) significantly enhanced p38 activation in HeLa cells[4]. Inhibition of WNK1 by WNK463(10 μM) leads to Ca2+ influx and permeability in lung endothelium via transient receptor potential vanilloid 4[5].
WNK blockade by WNK463 (1 mg/kg; oral in water;3days) decreases TRPV4 activity and expression in the aldosterone-sensitive distal nephron (ASDN) in mice[6]. WNK463 (8.57 mM, 100 μl, 0.857 μmol) administered via intra-hippocampal infusion for 7 days reduces KCC2-T1007 phosphorylation and restricts kainite (KA)-induced status epilepticus in vivo[3]. WNK1–OSR1 axis inhibitors WNK463(11μM,5μL; p.o; twice a week for a month) combined with oligo-fucoidan attenuate hepatocellular carcinoma (HCC) proliferation[7].
References:
[1]. Yamada K, Park HM, et,al. Small-molecule WNK inhibition regulates cardiovascular and renal function. Nat Chem Biol. 2016 Nov;12(11):896-898. doi: 10.1038/nchembio.2168. Epub 2016 Sep 5. PMID: 27595330.
[2]. Jonniya NA, Kar P. Investigating specificity of the anti-hypertensive inhibitor WNK463 against With-No-Lysine kinase family isoforms via multiscale simulations. J Biomol Struct Dyn. 2020 Mar;38(5):1306-1321. doi: 10.1080/07391102.2019.1602079. Epub 2019 Apr 24. PMID: 31017050.
[3]. Lee KL, Abiraman K, et,al. Inhibiting with-no-lysine kinases enhances K+/Cl- cotransporter 2 activity and limits status epilepticus. Brain. 2022 Apr 29;145(3):950-963. doi: 10.1093/brain/awab343. PMID: 34528073; PMCID: PMC9050525.
[4]. Liu Z, Demian W, et,al. Regulation of the p38-MAPK pathway by hyperosmolarity and by WNK kinases. Sci Rep. 2022 Aug 25;12(1):14480. doi: 10.1038/s41598-022-18630-w. PMID: 36008477; PMCID: PMC9411163.
[5]. Erfinanda L, Zou L, et,al. Loss of endothelial CFTR drives barrier failure and edema formation in lung infection and can be targeted by CFTR potentiation. Sci Transl Med. 2022 Dec 7;14(674):eabg8577. doi: 10.1126/scitranslmed.abg8577. Epub 2022 Dec 7. PMID: 36475904.
[6]. Tomilin VN, Pyrshev K, et,al. With-No-Lysine Kinase 1 (WNK1) Augments TRPV4 Function in the Aldosterone-Sensitive Distal Nephron. Cells. 2021 Jun 12;10(6):1482. doi: 10.3390/cells10061482. PMID: 34204757; PMCID: PMC8231605.
[7]. Hou CY, Ma CY, et,al. WNK1-OSR1 Signaling Regulates Angiogenesis-Mediated Metastasis towards Developing a Combinatorial Anti-Cancer Strategy. Int J Mol Sci. 2022 Oct 11;23(20):12100. doi: 10.3390/ijms232012100. PMID: 36292952; PMCID: PMC9602556.
WNK463是一种口服WNK激酶抑制剂，对WNK1、WNK2、WNK3和WNK4的IC50值分别为5 nM、1 nM、6 nM和9 nM [1-2]。
WNK463 (1 μM; 15 min)在HEK-293细胞中降低KCC2 1007位点磷酸化，提高KCC2活性[3]。WNK463 (10 μM ;2h)显著增强HeLa细胞中p38的激活[4]。WNK463(10 μM)对WNK1的抑制可通过瞬时受体电位香兰素4导致Ca2+内流和肺内皮通透性[5]。
WNK463阻断WNK (1 mg/kg;3d)降低小鼠醛固酮敏感远端肾元(ASDN)中TRPV4的活性和表达[6]。WNK463 (100 μl WNK463 (8.57 mM) (0.857μmol); intra hippocampal infusion;7days)在体内降低KCC2-T1007磷酸化并限制kainite(KA)诱导的癫痫持续状态[3]。WNK1-OSR1轴抑制剂WNK463 (11μM,5μL; p.o; twice a week for a month)联合寡聚岩藻多糖可减弱肝细胞癌增殖[7]。
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Cell experiment [1]: |
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Cell lines |
HEK-293 cells |
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Preparation method |
Cells transfected with hKCC2 cDNA plasmids were treated with either WNK463 (1 μM) or DMSO (0.1%) for 15 minutes at 37℃, three days post-transfection. |
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Reaction Conditions |
1 μM; 15 min |
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Applications |
WNK463 decreased K+/Cl- cotransporter 2 (KCC2) phosphorylation and increased KCC2 activity in HEK-293 cells. |
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Animal experiment [1]: |
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Animal models |
C57BL/6 male mice (Alzet pump implantation surgeries) |
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Preparation method |
Mini-osmotic pumps were loaded with 100 μl WNK463 (8.57 mM) or DMSO (14.2%) and connected to brain infusion kit. The rate of drug delivery by the Alzet osmotic pumps was 0.25 µl/h, resulting in final concentrations of 60 µM WNK463 and 0.1% DMSO in the brain. |
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Dosage form |
100 μl WNK463 (8.57 mM) (0.857μmol); intra hippocampal infusion;7days |
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Applications |
WNK463 reduces KCC2 phosphorylation in vivo. |
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References: [1]. Lee KL, Abiraman K, et,al. Inhibiting with-no-lysine kinases enhances K+/Cl- cotransporter 2 activity and limits status epilepticus. Brain. 2022 Apr 29;145(3):950-963. doi: 10.1093/brain/awab343. PMID: 34528073; PMCID: PMC9050525. |
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| Cas No. | 2012607-27-9 | SDF | |
| Canonical SMILES | FC(F)(F)C1=NN=C(O1)C2=CN=C(N3CCC(N4C=NC=C4C(NC(C)(C)C)=O)CC3)C=C2 | ||
| 分子式 | C21H24F3N7O2 | 分子量 | 463.46 |
| 溶解度 | DMSO : ≥ 30 mg/mL (64.73 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1577 mL | 10.7884 mL | 21.5768 mL |
| 5 mM | 0.4315 mL | 2.1577 mL | 4.3154 mL |
| 10 mM | 0.2158 mL | 1.0788 mL | 2.1577 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet