Small-molecule WNK inhibition regulates cardiovascular and renal function

September 5th, 2016 by Ken Yamada

Nature Chemical Biology 12, 896 (2016). doi:10.1038/nchembio.2168

Authors: Ken Yamada, Hyi-Man Park, Dean F Rigel, Keith DiPetrillo, Erin J Whalen, Anthony Anisowicz, Michael Beil, James Berstler, Cara Emily Brocklehurst, Debra A Burdick, Shari L Caplan, Michael P Capparelli, Guanjing Chen, Wei Chen, Bethany Dale, Lin Deng, Fumin Fu, Norio Hamamatsu, Kouki Harasaki, Tracey Herr, Peter Hoffmann, Qi-Ying Hu, Waan-Jeng Huang, Neeraja Idamakanti, Hidetomo Imase, Yuki Iwaki, Monish Jain, Jey Jeyaseelan, Mitsunori Kato, Virendar K Kaushik, Darcy Kohls, Vidya Kunjathoor, Daniel LaSala, Jongchan Lee, Jing Liu, Yang Luo, Fupeng Ma, Ruowei Mo, Sarah Mowbray, Muneto Mogi, Flavio Ossola, Pramod Pandey, Sejal J Patel, Swetha Raghavan, Bahaa Salem, Yuka H Shanado, Gary M Trakshel, Gordon Turner, Hiromichi Wakai, Chunhua Wang, Stephen Weldon, Jennifer B Wielicki, Xiaoling Xie, Lingfei Xu, Yukiko I Yagi, Kayo Yasoshima, Jianning Yin, David Yowe, Ji-Hu Zhang, Gang Zheng & Lauren Monovich

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.

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