WNK Signaling Inhibitors as Potential Antihypertensive Drugs

5 years ago

WNK Signaling Inhibitors as Potential Antihypertensive Drugs

Shumail Mahmood, Mubarak A. AlAmri, Hachemi Kadri, Binar A. Dhiani, Youcef Mehellou, Abdulrahman Elzwawi

Since the discovery of WNK mutations that cause an inherited form of hypertension in humans, there has been increasing interest in targeting WNK signaling as a novel strategy for modulating blood pressure. This notion is now supported by numerous mouse models with impaired WNK signaling that exhibit reduced blood pressure. Biochemical analyses of the various protein components that make up this signaling pathway have identified a number of plausible molecular targets that are amenable to targeting by small molecules. To date, a selection of small-molecule WNK signaling inhibitors have been identified and have shown promise in suppressing the activity of WNK signaling in cells and in animals. In this Minireview, we briefly discuss the WNK signaling pathway and provide an overview of the various druggable targets within this cascade, as well as the different WNK signaling inhibitors discovered to date. Various components of the WNK signaling cascade have been validated in vivo as viable targets for antihypertensive drugs. A selection of kinase and protein–protein interaction inhibitors, which have shown great promise in lowering blood pressure in vivo, have been reported. Herein we provide insight into the discovery the various reported WNK signaling inhibitors and offer an outlook into the future of targeting the WNK signaling pathway.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/cmdc.201700425