FDA-approved drugs as PIM-1 kinase inhibitors: A drug repurposed approach for cancer therapy.

PIM-1 kinase, a member of the Serine/Threonine kinase family, has emerged as a promising therapeutic target in various cancers due to its role in promoting tumor growth and resistance to conventional therapies. In this study, we employed a structure-based approach to screen 3800 FDA-approved drugs to discover potential inhibitors of PIM-1. After an initial selection of 50 candidates based on high docking scores, four drugs, stanozolol, alfaxalone, rifaximin, and telmisartan, were identified as strong PIM-1 binders, interacting with key residues in the ATP-binding pocket of the kinase. To assess the stability of these interactions, we conducted all-atom molecular dynamic simulations, confirming favorable dynamics. Experimental validation via a kinase inhibition assay on recombinant PIM-1 showed that rifaximin significantly inhibited PIM-1 activity, with an IC of ∼26 μM. Fluorescence binding assays further demonstrated a strong binding affinity for rifaximin, with a binding constant, corroborated by isothermal titration calorimetry studies. Our findings suggest that rifaximin may serve as a potential repurposed drug for targeting PIM-1 in cancer treatment. However, further validations are required in a clinical setting before the final therapeutic implications.