The Photosensitizing Clinical Agent Verteporfin is an Inhibitor of SPAK and OSR1 Kinases

SPAK and OSR1 are two serine/threonine protein kinases that play important key roles in regulating ion homeostasis. Various SPAK and OSR1 mouse models exhibited reduced blood pressure. Herein, we report the discovery of Verteporfin, a photosensitizing agent used in photodynamic therapy, as a potent inhibitor of SPAK and OSR1 kinases. We show that Verteporfin binds the kinase domains of SPAK and OSR1 and inhibit their catalytic activity in an ATP-independent manner. In cells, Verteporfin was able to suppress the phosphorylation of the ion co-transporter NKCC1, a downstream physiological substrate of SPAK and OSR1 kinases. Kinase panel screening indicated that Verteporfin inhibited a further eight protein kinases more potently than SPAK and OSR1. Although Verteporfin has largely been studied as a modifier of the Hippo signaling pathway, this work indicates that the WNK-SPAK/OSR1 signaling cascade is also a target of this clinical agent. This finding could explain the fluctuation in blood pressure noted in patients and animals treated with this drug.