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Title: Small-molecule WNK inhibition regulates cardiovascular and renal function

Abstract

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.


Citation Formats

Yamada, Ken, Park, Hyi-Man, Rigel, Dean F., DiPetrillo, Keith, Whalen, Erin J., Anisowicz, Anthony, Beil, Michael, Berstler, James, Brocklehurst, Cara Emily, Burdick, Debra A., Caplan, Shari L., Capparelli, Michael P., Chen, Guanjing, Chen, Wei, Dale, Bethany, Deng, Lin, Fu, Fumin, Hamamatsu, Norio, Harasaki, Kouki, Herr, Tracey, Hoffmann, Peter, Hu, Qi-Ying, Huang, Waan-Jeng, Idamakanti, Neeraja, Imase, Hidetomo, Iwaki, Yuki, Jain, Monish, Jeyaseelan, Jey, Kato, Mitsunori, Kaushik, Virendar K., Kohls, Darcy, Kunjathoor, Vidya, LaSala, Daniel, Lee, Jongchan, Liu, Jing, Luo, Yang, Ma, Fupeng, Mo, Ruowei, Mowbray, Sarah, Mogi, Muneto, Ossola, Flavio, Pandey, Pramod, Patel, Sejal J., Raghavan, Swetha, Salem, Bahaa, Shanado, Yuka H., Trakshel, Gary M., Turner, Gordon, Wakai, Hiromichi, Wang, Chunhua, Weldon, Stephen, Wielicki, Jennifer B., Xie, Xiaoling, Xu, Lingfei, Yagi, Yukiko I., Yasoshima, Kayo, Yin, Jianning, Yowe, David, Zhang, Ji-Hu, Zheng, Gang, and Monovich, Lauren. Small-molecule WNK inhibition regulates cardiovascular and renal function. United States: N. p., 2016. Web. doi:10.1038/nchembio.2168.
Yamada, Ken, Park, Hyi-Man, Rigel, Dean F., DiPetrillo, Keith, Whalen, Erin J., Anisowicz, Anthony, Beil, Michael, Berstler, James, Brocklehurst, Cara Emily, Burdick, Debra A., Caplan, Shari L., Capparelli, Michael P., Chen, Guanjing, Chen, Wei, Dale, Bethany, Deng, Lin, Fu, Fumin, Hamamatsu, Norio, Harasaki, Kouki, Herr, Tracey, Hoffmann, Peter, Hu, Qi-Ying, Huang, Waan-Jeng, Idamakanti, Neeraja, Imase, Hidetomo, Iwaki, Yuki, Jain, Monish, Jeyaseelan, Jey, Kato, Mitsunori, Kaushik, Virendar K., Kohls, Darcy, Kunjathoor, Vidya, LaSala, Daniel, Lee, Jongchan, Liu, Jing, Luo, Yang, Ma, Fupeng, Mo, Ruowei, Mowbray, Sarah, Mogi, Muneto, Ossola, Flavio, Pandey, Pramod, Patel, Sejal J., Raghavan, Swetha, Salem, Bahaa, Shanado, Yuka H., Trakshel, Gary M., Turner, Gordon, Wakai, Hiromichi, Wang, Chunhua, Weldon, Stephen, Wielicki, Jennifer B., Xie, Xiaoling, Xu, Lingfei, Yagi, Yukiko I., Yasoshima, Kayo, Yin, Jianning, Yowe, David, Zhang, Ji-Hu, Zheng, Gang, & Monovich, Lauren. Small-molecule WNK inhibition regulates cardiovascular and renal function. United States. doi:10.1038/nchembio.2168.
Yamada, Ken, Park, Hyi-Man, Rigel, Dean F., DiPetrillo, Keith, Whalen, Erin J., Anisowicz, Anthony, Beil, Michael, Berstler, James, Brocklehurst, Cara Emily, Burdick, Debra A., Caplan, Shari L., Capparelli, Michael P., Chen, Guanjing, Chen, Wei, Dale, Bethany, Deng, Lin, Fu, Fumin, Hamamatsu, Norio, Harasaki, Kouki, Herr, Tracey, Hoffmann, Peter, Hu, Qi-Ying, Huang, Waan-Jeng, Idamakanti, Neeraja, Imase, Hidetomo, Iwaki, Yuki, Jain, Monish, Jeyaseelan, Jey, Kato, Mitsunori, Kaushik, Virendar K., Kohls, Darcy, Kunjathoor, Vidya, LaSala, Daniel, Lee, Jongchan, Liu, Jing, Luo, Yang, Ma, Fupeng, Mo, Ruowei, Mowbray, Sarah, Mogi, Muneto, Ossola, Flavio, Pandey, Pramod, Patel, Sejal J., Raghavan, Swetha, Salem, Bahaa, Shanado, Yuka H., Trakshel, Gary M., Turner, Gordon, Wakai, Hiromichi, Wang, Chunhua, Weldon, Stephen, Wielicki, Jennifer B., Xie, Xiaoling, Xu, Lingfei, Yagi, Yukiko I., Yasoshima, Kayo, Yin, Jianning, Yowe, David, Zhang, Ji-Hu, Zheng, Gang, and Monovich, Lauren. Mon . "Small-molecule WNK inhibition regulates cardiovascular and renal function". United States. doi:10.1038/nchembio.2168.
@article{osti_1404999,
title = {Small-molecule WNK inhibition regulates cardiovascular and renal function},
author = {Yamada, Ken and Park, Hyi-Man and Rigel, Dean F. and DiPetrillo, Keith and Whalen, Erin J. and Anisowicz, Anthony and Beil, Michael and Berstler, James and Brocklehurst, Cara Emily and Burdick, Debra A. and Caplan, Shari L. and Capparelli, Michael P. and Chen, Guanjing and Chen, Wei and Dale, Bethany and Deng, Lin and Fu, Fumin and Hamamatsu, Norio and Harasaki, Kouki and Herr, Tracey and Hoffmann, Peter and Hu, Qi-Ying and Huang, Waan-Jeng and Idamakanti, Neeraja and Imase, Hidetomo and Iwaki, Yuki and Jain, Monish and Jeyaseelan, Jey and Kato, Mitsunori and Kaushik, Virendar K. and Kohls, Darcy and Kunjathoor, Vidya and LaSala, Daniel and Lee, Jongchan and Liu, Jing and Luo, Yang and Ma, Fupeng and Mo, Ruowei and Mowbray, Sarah and Mogi, Muneto and Ossola, Flavio and Pandey, Pramod and Patel, Sejal J. and Raghavan, Swetha and Salem, Bahaa and Shanado, Yuka H. and Trakshel, Gary M. and Turner, Gordon and Wakai, Hiromichi and Wang, Chunhua and Weldon, Stephen and Wielicki, Jennifer B. and Xie, Xiaoling and Xu, Lingfei and Yagi, Yukiko I. and Yasoshima, Kayo and Yin, Jianning and Yowe, David and Zhang, Ji-Hu and Zheng, Gang and Monovich, Lauren},
abstractNote = {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.},
doi = {10.1038/nchembio.2168},
journal = {Nature Chemical Biology},
number = 11,
volume = 12,
place = {United States},
year = {Mon Sep 05 00:00:00 EDT 2016},
month = {Mon Sep 05 00:00:00 EDT 2016}
}