Leveraging unique structural characteristics of WNK kinases to achieve therapeutic inhibition.
The with-no-lysine (K) WNK kinases are master regulators of the Na+-(K+)-Cl-cotransporters, including the renal-specific NCC and NKCC2 cotransporters. The discovery of WNK463, an orally bioavailable pan-WNK kinase inhibitor that exploits unique structural properties of the WNK catalytic domain to achieve high affinity and kinase selectivity, illustrates a strategy of leveraging distinct kinase features to develop specific inhibitors and validates the genetic predictions of the in vivo pharmacology of WNK inhibition.
MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
Jinwei
J
Zhang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Xianming
X
Deng
Department of Cellular and Molecular Physiology and Centers for Mendelian Genomics, Yale School of Medicine, New Haven, CT 06510, USA. kristopher.kahle@yale.edu.
Kristopher T
KT
Kahle
D000818:Animals; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011759:Pyrrolidines / Q000627:therapeutic use*; D064466:Solute Carrier Family 12, Member 1 / Q000235:genetics / Q000378:metabolism
D007093:Imidazoles; D011759:Pyrrolidines; C578714:SLC12A1 protein, human; D064466:Solute Carrier Family 12, Member 1; C000618759:WNK463; D017346:Protein Serine-Threonine Kinases