Discovery and Characterization of Allosteric WNK Kinase Inhibitors
2016
Protein kinases are known for their highly conserved
adenosine triphosphate(ATP)-binding site, rendering the discovery of selective inhibitors a major challenge. In theory, allosteric inhibitors can achieve high selectivity by targeting less conserved regions of the kinases, often with an added benefit of retaining efficacy under high physiological ATP concentration. Although often overlooked in favor of ATP-site directed approaches, performing a screen at high ATP concentration or stringent hit triaging with high ATP concentration offers conceptually simple methods of identifying inhibitors that bind outside the ATP pocket. Here, we applied the latter approach to the With-No-Lysine (K) (WNK) kinases to discover lead molecules for a next-generation antihypertensive that requires a stringent safety profile. This strategy yielded several ATP noncompetitive
WNK1–4 kinase inhibitors, the optimization of which enabled cocrystallization with
WNK1, revealing an allosteric binding mode consistent with the observ...
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