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Towards the Development of Small‐Molecule MO25 Binders as Potential Indirect SPAK/OSR1 Kinase Inhibitors
Author(s) -
Kadri Hachemi,
Alamri Mubarak A.,
Navratilova Iva H.,
Alderwick Luke J.,
Simpkins Nigel S.,
Mehellou Youcef
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600620
Subject(s) - small molecule , kinase , chemistry , phosphorylation , biochemistry , protein kinase a , in vitro , transporter , microbiology and biotechnology , biology , gene
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.