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

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Colleges, School and Institutes

Abstract

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.

Details

Original languageEnglish
JournalChemBioChem
Early online date12 Jul 2018
Publication statusE-pub ahead of print - 12 Jul 2018

Keywords

  • SPAK, OSR1, WNK, High throughput, Inhibitor