WITH NO LYSINE Kinases(WNK Kinases) are serine/threonine kinases uniquely characterized by an anomalous placement of a catalytic lysine, hence their moniker. In animals, WNK protein kinases play critical roles in protein trafficking of components that mediate renal ion transport processes and regulate osmoregulation of cell volume. In plants, the WNK kinase gene family is larger and more diverse. Recent studies revealed WNK kinase roles in orchestrating the trafficking of an ion channel, a lipid kinase complex in animals, and a heterotrimeric G protein signaling component in plants that is necessary for signal transduction. For this reason, new attention is geared toward investigating the mechanisms adopted by WNK kinases to nudge intracellular proteins to their destinations.
In this review, the functions of WNK kinases in protein trafficking are derived from what we have learned from the model organism Arabidopsis thaliana. To place this new idea in context, we provide the predicted WNK kinase structures, their predicted expression patterns, a speculated evolutionary pathway, and the regulatory roles of plant WNKs in transport processes and other physiologies. We brazenly predict that the WNK kinases in both plants and animals will soon be recognized as a nexus for trafficking‐based signal transduction.
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The first, potent, selective, and orally bioavailable pan With-No-Lysine (WNK) Kinase catalytic activity inhibitor with IC50 of 5/1/6/9 nM for WNK1/2/3/4, respectively; shows >50% inhibition against only 2 out of 442 human kinases at 10 uM; affects blood pressure and body fluid and electro-lyte homeostasis in rodent models of hypertension.
WNK inhibitor 11
WNK inhibitor 11 is a potent, selectiive and orally active inhibitor of WNK1 kinase with IC50 of 6 nM, 1,000-fold selectivity over WNK4 and 57-fold selectivity over WNK2; shows excellent selectivity with only a few significant off-target kinase inhibitions, most notably BTK and FER kinase; reduces blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats.
WNK inhibitor 7
A potent, selectiive inhibitor of WNK1 kinase with IC50 of 95 nM, shows IC50 of 1.39 uM in the cellular OSR1 phosphorylation assay with reasonable aqueous solubility.
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