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]。