Primair aldosteronisme: kleine molecuulantagonisten van gemuteerde KCNJ5-kaliumkanalen

BACKGROUND:Mutations in theKCNJ5(potassium inwardly rectifying channel subfamily J member 5) gene, encoding an inwardly rectifying potassium channel, can drive aldosterone overproduction in a subset of aldosterone-producing adenomas and in familial hyperaldosteronism type III. Our objective was to identify small molecule compounds that specifically antagonize mutant KCNJ5 channels.METHODS:Virtual screening of over 6 million small molecules identified compounds that putatively bind to KCNJ5 channels. The effect of 108 of these candidates was evaluated in vitro in human adrenocortical cells (HAC15) with inducible expression of wild-type or mutated forms ofKCNJ5. Assessment encompassed cell viability, flow cytometry, gene expression, and adrenal steroid quantification via liquid chromatography–tandem mass spectrometry.RESULTS:Compounds antagonizing mutated KCNJ5 function were identified by evaluating their ability to rescue adrenal cell death induced by overexpression of mutantKCNJ5. A sp