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

Ozhathil, Lijo Cherian; Delalande, Clémence Marie Sandrine; Bianchi, Beatrice; Nemeth, Gabor; Kappel, Sven; Thomet, Urs; Ross, Daniela; Simonin, Céline; Rubin, Matthias; Gertsch, Jürg; Lochner, Martin; Peinelt, Christine; Reymond, Jean-Louis; Abriel, Hugues (2018). Identification of potent and selective small molecule inhibitors of the cation channel TRPM4. British journal of pharmacology, 175(12), pp. 2504-2519. Wiley-Blackwell 10.1111/bph.14220

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BACKGROUND AND PURPOSE: TRPM4 is a calcium-activated nonselective 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 inhibitor 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 HTS 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 show for the first time that a naturally occurring variant of TRPM4, which display 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, the most 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
08 Faculty of Science > Departement of Chemistry and Biochemistry
04 Faculty of Medicine > Other Institutions > NCCR TransCure

UniBE Contributor:

Ozhathil, Lijo Cherian; Delalande, Clémence Marie Sandrine; Bianchi, Beatrice; Kappel, Sven; Thomet, Urs; Ross, Daniela; Simonin, Céline; Rubin, Matthias; Gertsch, Jürg; Lochner, Martin; Peinelt, Christine; Reymond, Jean-Louis and Abriel, Hugues

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
500 Science > 540 Chemistry

ISSN:

0007-1188

Publisher:

Wiley-Blackwell

Funders:

[4] Swiss National Science Foundation
[65] NCCR TransCure

Language:

English

Submitter:

Martin Lochner

Date Deposited:

24 Apr 2018 12:41

Last Modified:

27 Mar 2019 02:30

Publisher DOI:

10.1111/bph.14220

PubMed ID:

29579323

BORIS DOI:

10.7892/boris.114469

URI:

https://boris.unibe.ch/id/eprint/114469

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