The CaSR—GSH Interaction: Finding an Effective Antagonist

Overview

As the second leading cause of death, cancer has negatively impacted the lives of millions across the globe both directly and indirectly. In this study, we aim to stunt the rapid proliferation of cancer cells by targeting the interaction between the Calcium-Sensitive Receptor (CaSR) and Glutathione (GSH). Cancerous cells tend to release large amounts of GSH, an antioxidant, to counteract high metabolic activity, and this GSH activates CaSR, leading to an increase in proliferation of endothelial cells and, therefore, angiogenesis and vascularization of cancerous tissue. We hypothesize that quinazolinone derivatives, which recent publications have shown to have high inhibitory potential against CaSR, can bind to CaSR and outcompete endogenous agonists, thereby, abrogating GSH-mediated CaSR activation and stunting cancer cell proliferation. Computational drug repurposing methodology was used to create a compound library of quinazolinone-containing drugs, which were screened for binding potential to CaSR using AutoDock Vina. The highest ranked drug based on binding affinity, intermolecular interactions, and pharmacological analysis was chosen for in vitro validation. Luciferase assays and BRET Assays were performed on a stably transfected line of HEK-293 cells to determine efficacy of the drug in inhibiting CaSR activation. In this study, we highlight the potential of Idelalisib as an inhibitor of CaSR—GSH mediated downstream signaling responses such as endothelial cell proliferation in silico and in vitro and provide further evidence for the pre-clinical development of quinazolinone-containing compounds as CaSR inhibitors.