Identification of a Class of WNK Isoform-Specific Inhibitors Through High-Throughput Screening

Chlebowicz, Julita; Akella, Radha; Humphreys, John M.; He, Haixia; Kannangara, Ashari R.; Wei, Shuguang; Posner, Bruce; Goldsmith, Elizabeth J.

doi:10.2147/dddt.s389461

Identification of a Class of WNK Isoform-Specific Inhibitors Through High-Throughput Screening

Journal Article · Sun Jan 01 00:00:00 EST 2023 · Drug Design, Development and Therapy

DOI:https://doi.org/10.2147/dddt.s389461· OSTI ID:2470042

; ; ; ; Kannangara, Ashari R.; Wei, Shuguang; Posner, Bruce;

Introduction: WNK [with no lysine (K)] kinases are serine/threonine kinases associated with familial hyperkalemic hypertension (FHHt). WNKs are therapeutic targets for blood pressure regulation, stroke and several cancers including triple negative breast cancer and glioblastoma. Here, we searched for and characterized novel WNK kinase inhibitors. Methods: We used a ~210,000-compound library in a high-throughput screen, re-acquisition and assay, commercial specificity screens and crystallography to identify WNK-isoform-selective inhibitors. Results: We identified five classes of compounds that inhibit the kinase activity of WNK1: quinoline compounds, halo-sulfones, cyclopropane-containing thiazoles, piperazine-containing compounds, and nitrophenol-derived compounds. The compounds are strongly pan-WNK selective, inhibiting all four WNK isoforms. A class of quinoline compounds was identified that further shows selectivity among the WNK isoforms, being more potent toward WNK3 than WNK1. The crystal structure of the quinoline-derived SW120619 bound to the kinase domain of WNK3 reveals active site binding, and comparison to the WNK1 structure reveals the potential origin of isoform specificity. Discussion: The newly discovered classes of compounds may be starting points for generating pharmacological tools and potential drugs treating hypertension and cancer.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470042

Journal Information:: Drug Design, Development and Therapy, Journal Name: Drug Design, Development and Therapy Vol. 17; ISSN 1177-8881

Publisher:: Dove Medical PressCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Pharmacology & Pharmacy
WNK
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crystallography
inhibition screen
kinase inhibitor
structure–activity relationship

Identification of a Class of WNK Isoform-Specific Inhibitors Through High-Throughput Screening

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