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Towards the development of small molecule MO25-binders as potential indirect SPAK/OSR1 kinase inhibitors

Kadri, Hachemi, AlAmri, Mubarak A, Navratilova, Iva H, Alderwick, Luke J, Simpkins, Nigel S and Mehellou, Youcef 2017. Towards the development of small molecule MO25-binders as potential indirect SPAK/OSR1 kinase inhibitors. Chembiochem 18 (5) , pp. 460-465. 10.1002/cbic.201600620

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Abstract

The binding of the scaffolding protein MO25 to SPAK and OSR1 protein kinases, which regulate ion homeostasis, causes up to 100-fold increase in their catalytic activity. Since various animal models showed that the inhibition of SPAK and OSR1 lowers blood pressure, we herein present a novel indirect approach for inhibiting SPAK and OSR1 kinases by targeting their protein partner MO25. To explore this approach, we developed fluorescent polarization assay and used it in screening a small in-house library of  4,000 compounds. This led to the identification of one molecule, HK01, as the first small molecule inhibitor of the MO25-dependent activation of SPAK and OSR1 in vitro. Our data confirms the feasibility of targeting this protein-protein interaction by small molecules and highlights the potential of these molecules to modulate ion cotransporters and thus cellular electrolyte balance.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: MO25; Scaffolding; inhibitor; SPAK; OSR1
Publisher: Wiley
ISSN: 1439-4227
Date of First Compliant Deposit: 4 January 2017
Date of Acceptance: 22 December 2016
Last Modified: 30 Jan 2018 06:18
URI: http://orca.cf.ac.uk/id/eprint/97175

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