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Julita Chlebowicz,1 Radha Akella,1 John M Humphreys,1 Haixia He,1 Ashari R Kannangara,1 Shuguang Wei,2 Bruce Posner,2 Elizabeth J Goldsmith1 1Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX, USA; 2Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USACorrespondence: Elizabeth J Goldsmith, Department of Biophysics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-8816, USA, Tel +1 214 645 6376, Email Elizabeth.goldsmith@utsouthwestern.eduIntroduction: 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.Graphical Abstract: Keywords: WNK, inhibition screen, kinase inhibitor, WNK3-specific, structure–activity relationship, crystallography