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Rafoxanide and Closantel inhibit SPAK and OSR1 kinases by binding to a highly conserved allosteric site on their C-terminal domains

Alamri, Mubarak A, Kadri, Hachemi, Alderwick, Luke J, Simpkins, Nigel S and Mehellou, Youcef 2017. Rafoxanide and Closantel inhibit SPAK and OSR1 kinases by binding to a highly conserved allosteric site on their C-terminal domains. ChemMedChem 12 (9) , pp. 639-645. 10.1002/cmdc.201700077

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Abstract

SPAK and OSR1 are two protein kinases that emerged as attractive targets in the discovery of novel antihypertensive agents due to their role in regulating electrolyte balance in vivo. In this work, we report on the identification of an allosteric pocket on their highly conserved C-terminal domains, which influences their kinase activity. Also, we show that some known WNK-signaling inhibitors bind to this allosteric site. Using in silico screening, we identified Rafoxanide, an anti-parasitic agent, as a novel allosteric inhibitor of SPAK and OSR1. Collectively, this work will facilitate the rational design of novel SPAK and OSR1 kinase inhibitors that could be useful antihypertensive agents.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: allosteric inhibitors; hypertension; kinases; OSR1; SPAK
Publisher: Wiley-Blackwell
ISSN: 1860-7179
Date of First Compliant Deposit: 3 April 2017
Date of Acceptance: 2 April 2017
Last Modified: 27 Apr 2018 20:49
URI: http://orca-mwe.cf.ac.uk/id/eprint/99596

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