Structural highlights
Function
WNK3_HUMAN Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively (PubMed:16275913, PubMed:16275911, PubMed:16357011). Phosphorylates WNK4. Regulates the phosphorylation of SLC12A1 and SLC12A2. Increases Ca(2+) influx mediated by TRPV5 and TRPV6 by enhancing their membrane expression level via a kinase-dependent pathway (PubMed:18768590). Inhibits the activity of KCNJ1 by decreasing its expression at the cell membrane in a non-catalytic manner.[1] [2] [3] [4] [5] [6] [7] Isoform 1, isoform 2, isoform 3 and isoform 4 stimulate the activity of SLC12A1, SLC12A2 and SLC12A3 and inhibit the activity of SLC12A4, SLC12A5, SLC12A6 and SLC12A7. According to PubMed:19470686, isoform 1 inhibits the activity of SLC12A3.[8] [9]
Publication Abstract from PubMed
INTRODUCTION: WNK [with no lysine (K)] kinases are serine/threonine kinases associated with familial hyperkalemic hypertension (FHHt). WNKs are therapeutic targets for blood pressure regulation, stroke and several cancers including triple negative breast cancer and glioblastoma. Here, we searched for and characterized novel WNK kinase inhibitors. METHODS: We used a ~210,000-compound library in a high-throughput screen, re-acquisition and assay, commercial specificity screens and crystallography to identify WNK-isoform-selective inhibitors. RESULTS: We identified five classes of compounds that inhibit the kinase activity of WNK1: quinoline compounds, halo-sulfones, cyclopropane-containing thiazoles, piperazine-containing compounds, and nitrophenol-derived compounds. The compounds are strongly pan-WNK selective, inhibiting all four WNK isoforms. A class of quinoline compounds was identified that further shows selectivity among the WNK isoforms, being more potent toward WNK3 than WNK1. The crystal structure of the quinoline-derived SW120619 bound to the kinase domain of WNK3 reveals active site binding, and comparison to the WNK1 structure reveals the potential origin of isoform specificity. DISCUSSION: The newly discovered classes of compounds may be starting points for generating pharmacological tools and potential drugs treating hypertension and cancer.
Identification of a Class of WNK Isoform-Specific Inhibitors Through High-Throughput Screening.,Chlebowicz J, Akella R, Humphreys JM, He H, Kannangara AR, Wei S, Posner B, Goldsmith EJ Drug Des Devel Ther. 2023 Jan 20;17:93-105. doi: 10.2147/DDDT.S389461. , eCollection 2023. PMID:36712947[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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References
- ↑ Kahle KT, Rinehart J, de Los Heros P, Louvi A, Meade P, Vazquez N, Hebert SC, Gamba G, Gimenez I, Lifton RP. WNK3 modulates transport of Cl- in and out of cells: implications for control of cell volume and neuronal excitability. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16783-8. Epub 2005 Nov 7. PMID:16275911 doi:http://dx.doi.org/10.1073/pnas.0508307102
- ↑ Rinehart J, Kahle KT, de Los Heros P, Vazquez N, Meade P, Wilson FH, Hebert SC, Gimenez I, Gamba G, Lifton RP. WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16777-82. Epub 2005 Nov 7. PMID:16275913 doi:http://dx.doi.org/10.1073/pnas.0508303102
- ↑ Leng Q, Kahle KT, Rinehart J, MacGregor GG, Wilson FH, Canessa CM, Lifton RP, Hebert SC. WNK3, a kinase related to genes mutated in hereditary hypertension with hyperkalaemia, regulates the K+ channel ROMK1 (Kir1.1). J Physiol. 2006 Mar 1;571(Pt 2):275-86. Epub 2005 Dec 15. PMID:16357011 doi:http://dx.doi.org/10.1113/jphysiol.2005.102202
- ↑ Verissimo F, Silva E, Morris JD, Pepperkok R, Jordan P. Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway. Oncogene. 2006 Jul 13;25(30):4172-82. Epub 2006 Feb 27. PMID:16501604 doi:http://dx.doi.org/10.1038/sj.onc.1209449
- ↑ Yang CL, Zhu X, Ellison DH. The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. J Clin Invest. 2007 Nov;117(11):3403-11. PMID:17975670 doi:10.1172/JCI32033
- ↑ Zhang W, Na T, Peng JB. WNK3 positively regulates epithelial calcium channels TRPV5 and TRPV6 via a kinase-dependent pathway. Am J Physiol Renal Physiol. 2008 Nov;295(5):F1472-84. doi:, 10.1152/ajprenal.90229.2008. Epub 2008 Sep 3. PMID:18768590 doi:http://dx.doi.org/10.1152/ajprenal.90229.2008
- ↑ Heise CJ, Xu BE, Deaton SL, Cha SK, Cheng CJ, Earnest S, Sengupta S, Juang YC, Stippec S, Xu Y, Zhao Y, Huang CL, Cobb MH. Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members. J Biol Chem. 2010 Aug 13;285(33):25161-7. doi: 10.1074/jbc.M110.103432. Epub 2010, Jun 4. PMID:20525693 doi:10.1074/jbc.M110.103432
- ↑ Glover M, Zuber AM, O'Shaughnessy KM. Renal and brain isoforms of WNK3 have opposite effects on NCCT expression. J Am Soc Nephrol. 2009 Jun;20(6):1314-22. doi: 10.1681/ASN.2008050542. Epub 2009 , May 21. PMID:19470686 doi:http://dx.doi.org/10.1681/ASN.2008050542
- ↑ Cruz-Rangel S, Melo Z, Vazquez N, Meade P, Bobadilla NA, Pasantes-Morales H, Gamba G, Mercado A. Similar effects of all WNK3 variants on SLC12 cotransporters. Am J Physiol Cell Physiol. 2011 Sep;301(3):C601-8. doi:, 10.1152/ajpcell.00070.2011. Epub 2011 May 25. PMID:21613606 doi:http://dx.doi.org/10.1152/ajpcell.00070.2011
- ↑ Chlebowicz J, Akella R, Humphreys JM, He H, Kannangara AR, Wei S, Posner B, Goldsmith EJ. Identification of a Class of WNK Isoform-Specific Inhibitors Through High-Throughput Screening. Drug Des Devel Ther. 2023 Jan 20;17:93-105. PMID:36712947 doi:10.2147/DDDT.S389461
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