Discovery and Characterization of Allosteric WNK Kinase Inhibitors

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• 作者：Ken Yamada ; Ji-Hu Zhang ; Xiaoling Xie ; Juergen Reinhardt ; Amy Qiongshu Xie ; Daniel LaSala ; Darcy Kohls ; David Yowe ; Debra Burdick ; Hajime Yoshisue ; Hiromichi Wakai ; Isabel Schmidt ; Jason Gunawan ; Kayo Yasoshima ; Q. Kimberley Yue ; Mitsunori Kato ; Muneto Mogi ; Neeraja Idamakanti ; Natasha Kreder ; Peter Drueckes ; Pramod Pandey ; Toshio Kawanami ; Waanjeng Huang ; Yukiko I. Yagi ; Zhan Deng ; Hyi-Man Park
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：December 16, 2016
• 年：2016
• 卷：11
• 期：12
• 页码：3338-3346
• 全文大小：450K
• ISSN：1554-8937

文摘

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 observed exquisite specificity for WNK1–4 kinases. The optimized compound inhibited rubidium uptake by sodium chloride cotransporter 1 (NKCC1) in HT29 cells, consistent with the reported physiology of WNK kinases in renal electrolyte handling.