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

Mubarak Abdulrahman M Alamri, Hachemi Kadri, Luke Alderwick, Nigel Simpkins, Youcef Mehellou

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)
190 Downloads (Pure)

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.
Original languageEnglish
JournalChemMedChem
Early online date31 Mar 2017
DOIs
Publication statusE-pub ahead of print - 31 Mar 2017

Keywords

  • Kinase inhibitor
  • allosteric
  • SPAK
  • OSR1
  • WNK

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