Repurposing dronedarone for colorectal cancer therapeutic via suppression of the AKT/ERK signaling pathways

Colorectal cancer (CRC) remains one of the most prevalent and challenging cancers and advanced CRCs are resistant to targeted therapy, chemotherapy and immunotherapy. Therefore, it is urgent to develop new treatment strategies or therapeutic agents for CRC to improve clinical efficacy. Within the landscape of emerging therapeutic modalities, drug repurposing offers a particularly promising avenue for enhancing clinical outcomes. Herein, we revealed the functional repurposing of dronedarone, an FDA (the US Food and Drug Administration)-approved class III antiarrhythmic agent, demonstrating its potent anti-proliferative effects against CRC cells. Through rational drug structure modification, we synthesized thirteen dronedarone derivatives, among which derivative D4 demonstrated superior antiproliferative potency and lower toxicity both in vitro and in vivo. Mechanically, dronedarone and D4 induced mitochondrial dysfunction and suppressed both AKT (protein kinase B) and ERK (extracellular regulated protein kinase) signaling pathways simultaneously leading to CRC cells apoptosis. Collectively, our study sheds light on repurposing non-oncology drug dronedarone and its derivatives with their molecular mechanisms for CRC treatment.