title: Rafoxanide and Closantel Inhibit SPAK and OSR1 Kinases by Binding to a Highly Conserved Allosteric Site on Their C-terminal Domains.
abstract: SPAK and OSR1 are two protein kinases that have emerged as attractive targets in the discovery of novel antihypertensive agents due to their role in regulating electrolyte balance in vivo. Herein we report the identification of an allosteric pocket on the highly conserved C-terminal domains of these two kinases, which influences their activity. We also show that some known WNK signaling inhibitors bind to this allosteric site. Using in silico screening, we identified the antiparasitic agent rafoxanide as a novel allosteric inhibitor of SPAK and OSR1. Collectively, this work will facilitate the rational design of novel SPAK and OSR1 kinase inhibitors that could be useful antihypertensive agents.
authors.affiliation: School of Pharmacy, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Mubarak A
authors.initials: MA
authors.lastname: AlAmri
authors.affiliation: School of Pharmacy, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Hachemi
authors.initials: H
authors.lastname: Kadri
authors.affiliation: Birmingham Drug Discovery Facility, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Alderwick
authors.affiliation: School of Chemistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Simpkins
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Redwood Building, Cardiff University, Cardiff, CF10 3NB, UK.
authors.forename: Youcef
authors.identifier: 0000-0001-5720-8513
authors.initials: Y
authors.lastname: Mehellou
mesh_terms: D000495:Allosteric Site; D000595:Amino Acid Sequence; D002784:Cholesterol / Q000494:pharmacology*; D005454:Fluorescence Polarization; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011888:Rafoxanide / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011888:Rafoxanide; D002784:Cholesterol; C118135:OXSR1 protein, human; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human
keywords: OSR1; SPAK; allosteric inhibitors; hypertension; kinases