Structure-Based Design of UVRAG-BAX Binding Interface-Targeting Compound Induces Apoptosis and ROS in Breast Cancer Cells

Targeting protein-protein interaction interfaces has emerged as an effective strategy in modern Anticancer drug discovery, as these interfaces regulate critical signaling pathways involved in tumor progression and survival. In this study, a structure-based strategy was used to identify potential small-molecule inhibitors targeting the interaction interface of the UVRAG-BAX protein complex. Initially, the interaction interface between UVRAG and Bax was characterized using protein-protein docking. Subsequently, virtual screening of compounds from the ZINC database was carried out, followed by molecular docking to identify molecules capable of binding to the targeted interface region. Cytotoxicity analysis using the MTT assay showed a potent inhibitory effect with an IC₅₀ value of 5 ± 0.283 μM. Furthermore, mechanistic studies suggested that treatment with the compound significantly increased the intracellular level of Reactive Oxygen Species causing apoptotic cell death, arrested the cell cycle in S phase and elevated the Sub G₀ population in MCF-7 cells. Confocal microscopy using AO/DAPI staining further confirmed cell death in treated cells. These findings suggest that 1-[2-(4,11-dimethyl-2-oxo-6,7,8,9-tetrahydro-[1]benzofuro[3,2-g]chromen-3-yl)acetyl]-4-phenylpiperidine-4-carboxylic acid (ZINC000002107582) is a promising lead compound that targets the UVRAG interaction interface and exerts potent Anticancer effects in breast Cancer cells.