Multi-targeted Drug Repurposing Approach for Breast Cancer via Integrated Functional Network Analysis.

The present study focuses on the interconnected functional network of altered metabolism and EMT (epithelial to mesenchymal transition) signaling in breast cancer. We have interlinked the metabolic and EMT signaling circuits and selected Insulin receptor (IR), Integrin beta 1 (ITGB1), and CD36 as target proteins based on network analysis. Extensive computational approaches discerned the potential drug molecules from the library of 1293 FDA-approved drugs to block all three target proteins. Using molecular docking, molecular dynamics simulation, and MMPBSA binding free energy studies, Capmatinib, Ponatinib, Naldemedine, and Pimozide were identified as potential repurposed drugs to block the function of all three target proteins. Among in silico selected candidate drugs, Pimozide, a known anti-psychotic drug, was further validated using in-vitro studies for its anti-cell proliferative potential on breast cancer cell lines (namely, MCF7, MDAMB231 and MDAMB468). The inhibitory concentration (IC 50 ) values of MCF7, MDAMB231 and MDAMB468 was found to be 16.26 μM, 20.82 μM and 13.10 μM, respectively. The effect of Pimozide on EMT-induced MDAMB231 and MDAMB468 cells was evident from their IC 50 values of 7.85 μM and 6.83 μM, respectively. The potent anti-cancer property of Pimozide has opened up avenues for drug repurposing towards 'multi-targeted therapy' in EMT dynamics.