Computational drug repurposing for primary hyperparathyroidism

Abstract

In hyperparathyroidism (hyperPTH), excessive amounts of PTH are secreted, interfering with calcium regulation in the body. Several drugs can control the disease's side effects, but none of them is an alternative treatment to surgery. Therefore, new drug candidates are necessary. In this study, three computationally repositioned drugs, DG 041, IMD 0354, and cucurbitacin I, are evaluated in an in vitro model of hyperPTH. First, we integrated publicly available transcriptomics datasets to propose drug candidates. Using 3D spheroids derived from a single primary hyperPTH patient, we assessed their in vitro efficacy. None of the proposed drugs affected the viability of healthy cell control (HEK293) or overactive parathyroid cells at the level of toxicity. This behavior was attributed to the non-cancerous nature of the parathyroid cells, establishing the hyperPTH disease model. Cucurbitacin I and IMD 0354 exhibited a slight inverse relationship between increased drug concentrations and cell viability, whereas DG 041 increased viability. Based on these results, further studies are needed on the mechanism of action of the repurposed drugs, including determining the effects of these drugs on cellular PTH synthesis and secretion and on the metabolic pathways that regulate PTH secretion.