Small-molecule WNK inhibition regulates cardiovascular and renal function.
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.
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Ken
K
Yamada
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Hyi-Man
HM
Park
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Dean F
DF
Rigel
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Keith
K
DiPetrillo
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Erin J
EJ
Whalen
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Anthony
A
Anisowicz
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Michael
M
Beil
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
James
J
Berstler
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Cara Emily
CE
Brocklehurst
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Debra A
DA
Burdick
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Shari L
SL
Caplan
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Michael P
MP
Capparelli
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Guanjing
G
Chen
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Wei
W
Chen
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Bethany
B
Dale
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Lin
L
Deng
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Fumin
F
Fu
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Norio
N
Hamamatsu
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Kouki
K
Harasaki
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Tracey
T
Herr
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Peter
P
Hoffmann
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Qi-Ying
QY
Hu
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Waan-Jeng
WJ
Huang
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Neeraja
N
Idamakanti
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Hidetomo
H
Imase
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Yuki
Y
Iwaki
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Monish
M
Jain
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Jey
J
Jeyaseelan
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Mitsunori
M
Kato
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Virendar K
VK
Kaushik
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Darcy
D
Kohls
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Vidya
V
Kunjathoor
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Daniel
D
LaSala
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Jongchan
J
Lee
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Jing
J
Liu
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Yang
Y
Luo
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Fupeng
F
Ma
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Ruowei
R
Mo
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Sarah
S
Mowbray
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Muneto
M
Mogi
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Flavio
F
Ossola
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Pramod
P
Pandey
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Sejal J
SJ
Patel
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Swetha
S
Raghavan
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Bahaa
B
Salem
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Yuka H
YH
Shanado
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Gary M
GM
Trakshel
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Gordon
G
Turner
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Hiromichi
H
Wakai
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Chunhua
C
Wang
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Stephen
S
Weldon
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Jennifer B
JB
Wielicki
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Xiaoling
X
Xie
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Lingfei
L
Xu
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Yukiko I
YI
Yagi
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Kayo
K
Yasoshima
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Jianning
J
Yin
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
David
D
Yowe
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Ji-Hu
JH
Zhang
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Gang
G
Zheng
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Lauren
L
Monovich
D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007677:Kidney Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D054852:Small Molecule Libraries; C000618759:WNK463; D017346:Protein Serine-Threonine Kinases