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Chembiochem ; 18(5): 460-465, 2017 03 02.
Article in English | MEDLINE | ID: mdl-28004876

ABSTRACT

The binding of the scaffolding protein MO25 to SPAK and OSR1 protein kinases, which regulate ion homeostasis, causes increases of up to 100-fold in their catalytic activity. Various animal models have shown that the inhibition of SPAK and OSR1 lowers blood pressure, and so here we present a new indirect approach to inhibiting SPAK and OSR1 kinases by targeting their protein partner MO25. To explore this approach, we developed a fluorescent polarisation assay and used it in screening of a small in-house library of ≈4000 compounds. This led to the identification of one compound-HK01-as the first small-molecule inhibitor of the MO25-dependent activation of SPAK and OSR1 in vitro. Our data confirm the feasibility of targeting this protein-protein interaction by small-molecule compounds and highlights their potential to modulate ion co-transporters and thus cellular electrolyte balance.


Subject(s)
Phenylalanine/analogs & derivatives , Phthalimides/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Animals , Binding Sites , Biological Assay , Enzyme Activation/drug effects , HEK293 Cells , Humans , Immunoblotting , Mice , Phenylalanine/chemistry , Phenylalanine/metabolism , Phthalimides/metabolism , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/metabolism , Water-Electrolyte Balance/drug effects
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