Discovery of WNK-SPAK/OSR1 signalling inhibitors as potential therapeutics

Alamri, Mubarak (2018). Discovery of WNK-SPAK/OSR1 signalling inhibitors as potential therapeutics. University of Birmingham. Ph.D.

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Abstract

Protein kinases are major drug targets for many diseases. Among these are the STE20/SPS1-related proline/alanine-rich kinase (SPAK) and the oxidative- stress-responsive kinase 1 (OSR1), which are two related serine/threonine protein kinases. Both kinases are key components of the WNK-SPAK/OSR1 signalling pathway that has emerged as a key regulator of electrolyte homeostasis, body fluid and blood pressure. Various knock-in and knock-out SPAK and OSR1 mouse models exhibited reduced blood pressure. This highlighted SPAK and OSR1 kinases as promising targets in the treatment of hypertension.
Encouraged by this, this project was initiated to discover specific WNK-signalling inhibitors by targeting
SPAK and OSR1 kinases as potential novel antihypertensive agents. My work led to the identification of an allosteric pocket located in the highly conserved C-terminal domains of SPAK and OSR1, which influences their kinase activities. Using in silico screening, Rafoxanide, an anti-parasitic agent, was identified as a novel allosteric inhibitor of SPAK and OSR1. Additionally, high throughput screening led to the discovery of the clinically used agent, Verteporfin, as a novel and potent WNK-signalling inhibitor.
Moreover, several fragment-binders to the C-terminal domain of OSR1 kinase were identified using NMRfragment
based screening. In addition, the NMR backbone assignments of the C-terminal domain of OSR1 kinase were determined and used to map the previously unknown binding site of different OSR1 and SPAK inhibitors. Collectively, these findings have significantly advanced the field of SPAK and OSR1 kinase inhibition and provided key tools that will facilitate the future discovery of other SPAK and OSR1 kinase inhibitors.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Supervisor(s):
Supervisor(s)EmailORCID
Mehellou, YoucefUNSPECIFIEDUNSPECIFIED
Jeeves, MarkUNSPECIFIEDUNSPECIFIED
Licence:
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Clincal and Experimental Medicine, Department of Pharmacology and Therapeutics
Funders: None/not applicable
Subjects: Q Science > QD Chemistry
R Medicine > RS Pharmacy and materia medica
URI: http://etheses.bham.ac.uk/id/eprint/8559

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