Drug Repurposing Revealed Abemaciclib and Palbociclib as Inhibitor of Phosphodiesterase-5 (PDE5) in Cancer-Associated Fibroblasts Paving the Way for the Treatment of Breast Cancer

Background: A common element of the tumor microenvironment, cancer-associated fibroblasts play a major role in the development of breast cancer via a variety of pathways. Studies show that cancer-associated fibroblasts over express phosphodiesterase-5 in comparison to normal fibroblasts and that this overexpression is linked to increased fibroblast activation and a more aggressive CAF phenotype. High PDE5 levels in CAFs contribute to the remodeling of the extracellular matrix, increased secretion of pro-tumorigenic factors and suppression of anti-tumor immune responses. Materials and Methods: Targeting PDE5 in CAFs thus offers a convincing method to interfere with these cells' pro-tumorigenic activities. The potential to inhibit PDE5 was examined for four FDA-approved CDK4/6 inhibitors: Abemaciclib, Palbociclib, Alvocidib and Ribociclib. Results: These drugs, with established safety profiles, were screened and docked against PDE5, showing binding affinities of -7.8, -7.8, -7.1 and -6.8 kcal/mol, respectively, compared to Sildenafil's -7.0 kcal/mol, a known inhibitor of PDE5. ADMET predictions, PASS analysis and Swiss Target Prediction affirmed their drug-like properties and potential for PDE5 inhibition. Conclusion: Based on these results, Abemaciclib and Palbociclib were chosen for in vitro experiments with cancer-associated fibroblasts. The 2 drugs significantly decreased the expression of PDE5 mRNA, indicating their potential as therapeutic agents for the treatment of breast cancer.