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.
Antihypertensive agents: High‐throughput screening of a small library of 4000 compounds identified one of them—HK01—as a promising binder to the scaffolding protein MO25, able to inhibit MO25‐dependent activation of SPAK and OSR1 protein kinases in vitro and in cells. This approach could yield useful SPAK and OSR1 indirect kinase inhibitors.