A drug repurposing study identifies novel FOXM1 inhibitors with in vitro activity against breast cancer cells

FOXM1, a proto-oncogenic transcription factor, is crucial in cancer development and treatment resistance, particularly in breast cancer. This study aimed to discover potential FOXM1 inhibitors through computational drug screening, followed by in vitro validation of their effects on breast cancer cells. The in silico approach involved pharmacophore modeling using the known FOXM1 inhibitor, FDI-6, and subsequent virtual screening of the DrugBank and Selleckchem databases. The selected drugs underwent molecular docking preparation, with the FOXM1 crystal structure pre-processed for docking simulations. In vitro assays, including MTT tests to measure cytotoxicity and Western blot analysis to assess protein expression, were conducted to validate the findings. Pantoprazole and Rabeprazole emerged as potential FOXM1 inhibitors based on in silico screening and molecular docking results. Molecular dynamics simulations confirmed that these drugs form stable interactions with FOXM1. In vitro experiments demonstrated that both Pantoprazole and Rabeprazole effectively inhibited FOXM1 and reduced cell proliferation. Specifically, Rabeprazole exhibited inhibitory activity at 10 µM in BT-20 and MCF-7 cell lines, while Pantoprazole showed inhibition at 30 µM in BT-20 cells and at 70 µM in MCF-7 cells. This study provides the first evidence that Rabeprazole and Pantoprazole can bind to FOXM1, suppress its activity, and inhibit downstream signaling pathways, including eEF2K and pEF2, in breast cancer cells. These results suggest that Rabeprazole and Pantoprazole could be potential candidates for FOXM1-targeted therapy in breast cancer or other FOXM1-driven cancers.