Towards the Development of Small-Molecule MO25Binders as Potential Indirect SPAK/OSR1 Kinase Inhibitors

Research output: Contribution to journalArticle

Authors

Colleges, School and Institutes

Abstract

The binding of the scaffolding protein MO25 to SPAK andOSR1 protein kinases, which regu late ion homeostasis, causesincreases of up to 100-fold in their catalytic activity. Variousanimal models have shown that the inhibition of SPAK andOSR1 lowers blood pressure, andsohere we present anewindirect approachtoinhibiting SPAK and OSR1 kinases by tar-geting their protein partner MO25. To explorethis approach,we developed afluorescent polarisation assay and used it inscreening of asmall in-house library of &4000 compounds.This led to the identification of one compound—H K01—as thefirst small-molecule inhibitor of the MO25-dependent activa-tion of SPAK and OSR1 in vitro. Our data confirm the feasibilityof targeting this protein–protein interaction by small-moleculecompounds and highlights their potential to modulate ion co-transporters and thus cellular electrolyte balance.

Details

Original languageEnglish
Pages (from-to)460-465
JournalChemBioChem
Volume18
Issue number5
Early online date30 Jan 2017
Publication statusPublished - 2 Mar 2017

Keywords

  • high-throughput screening, inhibitors, MO25, OSR1, scaffolding, SPAK