Endocrine Abstracts

Primary aldosteronism (PA) is a form of endocrine hypertension characterized by autonomous aldosterone secretion. Aldosterone-producing adenomas (APAs) are a significant cause of unilateral PA, where aldosterone overproduction is driven by a somatic mutation in an ion pump or channel. Multiple studies have shown that mutations in the KCNJ5 gene are the most prevalent in PA patients suffering from the unilateral subtype, and unilateral laparoscopic total adrenalectomy is currently the preferred treatment strategy for these patients. Pharmacological intervention targeting mutated KCNJ5 channels could provide an alternative therapy for unilateral PA. Previous studies suggest that macrolides are potent inhibitors of mutated KCNJ5 channels. Nevertheless, for the treatment of PA patients, the potential induction of pathogen resistance through antibiotic treatment or increased gastrointestinal side effects through motilide activity would not be desirable (Scholl et al., 2017). We hypothesize that APAs carrying mutated KCNJ5 channels can be specifically targeted both via pharmacological channel inhibition as well as through pharmacological ablation of mutated cells. Therefore, we designed a study to identify small molecule compounds potentially applicable for the personalized treatment of a subset of PA patients. In silico screenings of over six million compounds detected small molecules structurally similar to the KCNJ5 channel pore, which were tested for their agonist and antagonist performance through different in vitro assays. The most promising antagonist candidates are currently being characterized to assess their effect on CYP11B2 expression and aldosterone levels. In contrast, agonist candidates are being further investigated for potential toxicity effects. A successful therapeutic outcome using a targeted pharmacological strategy could potentially replace surgical intervention.