English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

Background and Purpose  TRPM4 is a calcium‐activated non‐selective cation channel expressed in many tissues and implicated in several diseases, and has not yet been validated as a therapeutic target due to the lack of potent and selective inhibitors. We sought to discover a novel series of small‐molecule inhibitors by combining  in silico  methods and cell‐based screening assay, with sub‐micromolar potency and improved selectivity from previously reported TRPM4 inhibitors.    Experimental Approach  Here, we developed a high throughput screening compatible assay to record TRPM4‐mediated Na +  influx in cells using a Na + ‐sensitive dye and used this assay to screen a small set of compounds selected by ligand‐based virtual screening using previously known weakly active and non‐selective TRPM4 inhibitors as seed molecules. Conventional electrophysiological methods were used to validate the potency and selectivity of the hit compounds in HEK293 cells overexpressing TRPM4 and in endogenously expressing prostate cancer cell line LNCaP. Chemical chaperone property of compound  5  was studied using Western blots and electrophysiology experiments.    Key Results  A series of halogenated anthranilic amides were identified with TRPM4 inhibitory properties with sub‐micromolar potency and adequate selectivity. We also showed for the first time that a naturally occurring variant of TRPM4, which displays loss‐of‐expression and function, is rescued by the most promising compound  5  identified in this study.    Conclusions and Implications  The discovery of compound  5 , a potent and selective inhibitor of TRPM4 with an additional chemical chaperone feature, revealed new opportunities for studying the role of TRPM4 in human diseases and developing clinical drug candidates.

Identification of potent and selective small molecule inhibitors of the cation channel TRPM4