Targeting Ion Channel TRPM4

Preti, Barbara; Rougier, Jean-Sébastien; Papapostolou, Irida; Bochen, Florian; GERBER, CHRISTIAN; Abriel, Hugues; Lochner, Martin; Peinelt, Christine

doi:10.2533/chimia.2022.1039

Cited by 3 publications

(2 citation statements)

References 50 publications

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“…When, amongst other known weak and unspecific inhibitors, flufenamic acid is given as inhibitor template, LBVS identified 4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid (CBA), 4-chloro-2-(1-naphthyloxyacetamido) benzoic acid (NBA) and 4-chloro-2-(2-(4-chloro-2-methylphenoxy)propanamido) benzoic acid (LBA) as potential inhibitors ( Delalande et al, 2019 ). In fact, flufenamic acid inhibits transient potential melatonin 4 (TRPM4) ion channel and CBA, NBA and LBA could be identified as potent small molecule inhibitors of TRPM4 ( Ozhathil et al, 2018 ; Borgström et al, 2021a ; 2021b ; Stokłosa et al, 2021 ; Preti et al, 2022 ). CBA has been identified as specific inhibitor of TRPM4.…”

Section: Introductionmentioning

confidence: 99%

CBA (4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) inhibits TMEM206 mediated currents and TMEM206 does not contribute to acid-induced cell death in colorectal cancer cells

Kappel,

Melek,

Ross-Kaschitza

et al. 2024

Front. Pharmacol.

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Introduction: Upon activation at low pH, TMEM206 conducts Cl− ions across plasma and vesicular membranes. In a (patho)physiological context, TMEM206 was reported to contribute to acid-induced cell death in neurons, kidney and cervical epithelial cells. We investigated the role of TMEM206 in acid-induced cell death in colorectal cancer cells. In addition, we studied CBA as a new small molecule inhibitor for TMEM206.Methods: The role of TMEM206 in acid-induced cell death was studied with CRISPR/Cas9-mediated knockout and FACS analysis. The pharmacology of TMEM206 was determined with the patch clamp technique.Results: In colorectal cancer cells, TMEM206 is not a critical mediator of acid-induced cell death. CBA is a small molecule inhibitor of TMEM206 (IC50 = 9.55 µM) at low pH, at pH 6.0 inhibition is limited.Conclusion: CBA demonstrates effective and specific inhibition of TMEM206; however, its inhibitory efficacy is limited at pH 6.0. Despite this limitation, CBA is a potent inhibitor for functional studies at pH 4.5 and may be a promising scaffold for the development of future TMEM206 inhibitors.

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Section: Introductionmentioning

confidence: 99%

CBA (4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) inhibits TMEM206 mediated currents and TMEM206 does not contribute to acid-induced cell death in colorectal cancer cells

Kappel,

Melek,

Ross-Kaschitza

et al. 2024

Front. Pharmacol.

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“…In this paper, we report an optimized, efficient, cheap, and fast method for generating spheres derived from different human cancer cell lines. This method can be easily integrated into a 2D cell culture workflow in any laboratory and has previously been used by our group to generate spheres from the DU145 prostate cancer cell line [19]. The protocol described uses ultra-low-attachment (ULA) multiwell plates with U-bottoms for spheroid generation.…”

Section: Introductionmentioning

confidence: 99%

A Simple and Fast Method for the Formation and Downstream Processing of Cancer-Cell-Derived 3D Spheroids: An Example Using Nicotine-Treated A549 Lung Cancer 3D Spheres

Papapostolou,

Bochen,

Peinelt

et al. 2023

MPs

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Although 2D in vitro cancer cell cultures have been used for decades as a first line-of-research tool to investigate antitumoral drugs and treatments, their use presents many drawbacks, including the poor resemblance of such cultures to the characteristics of in vivo tumors. To mitigate these drawbacks, 3D culture models have emerged as a more representative alternative. Cancer cells cultured as 3D structures have the advantage of resembling solid tumors in their architecture and in their resistance to chemotherapeutic drugs, in part because of restrained drug penetration. Additionally, these 3D structures create a more physiological environment for the study of immune cell invasion and migration, comparable to solid tumors. In this paper, we describe a fast and cost-effective step-by-step protocol for the generation of 3D spheres using ultra-low-attachment (ULA) multiwell plates, which can be incorporated into the normal workflow of any laboratory. Using this protocol, spheroids of different human cancer cell lines can be obtained and can then be characterized on the basis of their morphology, viability, and expression of specific markers.

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CNS Drug Discovery in Academia: Where Basic Research Meets Innovation

Gertsch,

Chicca

2024

ChemBioChem

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The involvement of academic research in drug discovery is consistently growing. However, academic projects seldom advance to clinical trials. Here, we assess the landscape of drug discovery within the National Centre of Competence in Research (NCCR) TransCure launched by the Swiss National Science Foundation to foster basic research and early‐stage drug discovery on membrane transporters. This included transporters in central nervous system (CNS) disorders, which represent a huge unmet medical need. While idea championship, sustainable funding, collaborations between disciplines at the interface of academia and industry are important for translational research, Popperian falsifiability, strong intellectual property and a motivated startup team are key elements for innovation. This is exemplified by the NCCR TransCure spin‐off company Synendos Therapeutics, a clinical stage biotech company developing the first selective endocannabinoid reuptake inhibitors (SERIs) as novel treatment for neuropsychiatric disorders. We provide a perspective on the challenges related to entering an uncharted druggable space and bridging the often mentioned “valley of death”. The high attrition rate of drug discovery projects in the CNS field within academia is often due to the lack of meaningful animal models that can provide pharmacological proof‐of‐concept for potentially disruptive technologies at the earliest stages, and the absence of solid intellectual property.

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Targeting Ion Channel TRPM4

Cited by 3 publications

References 50 publications

CBA (4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) inhibits TMEM206 mediated currents and TMEM206 does not contribute to acid-induced cell death in colorectal cancer cells

CBA (4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) inhibits TMEM206 mediated currents and TMEM206 does not contribute to acid-induced cell death in colorectal cancer cells

A Simple and Fast Method for the Formation and Downstream Processing of Cancer-Cell-Derived 3D Spheroids: An Example Using Nicotine-Treated A549 Lung Cancer 3D Spheres

CNS Drug Discovery in Academia: Where Basic Research Meets Innovation

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