AUTHOR=Kappel Sven , Melek Korollus , Ross-Kaschitza Daniela , Hauert Barbara , Gerber Christian E. , Lochner Martin , Peinelt Christine 

TITLE=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

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1369513

DOI=10.3389/fphar.2024.1369513

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> Upon activation at low pH, TMEM206 conducts Cl<sup>−</sup> 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.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results:</bold> In colorectal cancer cells, TMEM206 is not a critical mediator of acid-induced cell death. CBA is a small molecule inhibitor of TMEM206 (IC<sub>50</sub> = 9.55 µM) at low pH, at pH 6.0 inhibition is limited.</p><p><bold>Conclusion:</bold> 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.</p>