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

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@article{a1c106357f2745aea7de3ed3fcdc1ca0,
title = "The Photosensitizing Clinical Agent Verteporfin is an Inhibitor of SPAK and OSR1 Kinases",
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.",
keywords = "SPAK, OSR1, WNK, High throughput, Inhibitor",
author = "Luke Alderwick and Mark Jeeves",
year = "2018",
month = jul
day = "12",
doi = "10.1002/cbic.201800272",
language = "English",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley-VCH Verlag",

}

RIS

TY - JOUR

T1 - The Photosensitizing Clinical Agent Verteporfin is an Inhibitor of SPAK and OSR1 Kinases

AU - Alderwick, Luke

AU - Jeeves, Mark

PY - 2018/7/12

Y1 - 2018/7/12

N2 - 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.

AB - 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.

KW - SPAK

KW - OSR1

KW - WNK

KW - High throughput

KW - Inhibitor

U2 - 10.1002/cbic.201800272

DO - 10.1002/cbic.201800272

M3 - Article

JO - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

ER -