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Identification of Kinase-substrate Pairs Using High Throughput Screening
Published on: August 29, 2015
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Identification of a Class of WNK Isoform-Specific Inhibitors Through High-Throughput Screening.
Julita Chlebowicz1, Radha Akella1, John M Humphreys1
1Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Drug Design, Development and Therapy
|January 30, 2023
Summary
Researchers identified novel WNK kinase inhibitors, including quinoline compounds, from a large library screen. These inhibitors show pan-WNK selectivity and may lead to new treatments for hypertension and cancer.
Area of Science:
- Biochemistry
- Pharmacology
Background:
- WNK (with no lysine) kinases are serine/threonine kinases implicated in familial hyperkalemic hypertension (FHHt).
- WNK kinases represent therapeutic targets for managing blood pressure, stroke, and various cancers like triple-negative breast cancer and glioblastoma.
Purpose of the Study:
- To identify and characterize novel inhibitors targeting WNK kinases.
- To discover compounds with potential therapeutic applications in hypertension and cancer treatment.
Main Methods:
- A high-throughput screening of approximately 210,000 compounds was conducted.
- Assays included re-acquisition, specificity screening, and crystallography to identify WNK-isoform-selective inhibitors.
Main Results:
- Five distinct classes of WNK1 inhibitors were identified: quinoline compounds, halo-sulfones, cyclopropane-containing thiazoles, piperazine-containing compounds, and nitrophenol-derived compounds.
- All identified compounds demonstrated broad selectivity, inhibiting all four WNK isoforms (pan-WNK selectivity).
- A subset of quinoline compounds exhibited specific potency towards WNK3 over WNK1, with structural analysis revealing the basis for this selectivity.
Conclusions:
- The newly discovered compound classes serve as potential starting points for developing pharmacological tools.
- These inhibitors hold promise for the development of novel therapeutic agents for hypertension and various cancers.
