Development of Niclosamide Prodrugs Preserves Wnt Inhibition and Anticancer Activity Through Rapid Bioactivation

Colorectal, lung, breast, and melanoma malignancies remain major contributors to cancer-related morbidity and mortality worldwide, underscoring the need for therapeutic strategies that can be rapidly translated to the clinic. Drug repurposing offers an attractive route for accelerating oncology drug development, particularly for agents with established safety profiles. Niclosamide, an FDA-approved anthelmintic, has demonstrated broad anticancer activity through modulation of Wnt1/β-catenin signaling and other pathways associated with tumor growth, metastasis, and therapeutic resistance. However, poor pharmaceutical and pharmacokinetic properties have limited its advancement as a systemic cancer therapeutic. To investigate prodrug-based approaches for improving niclosamide delivery, we synthesized a panel of ester and carbonate derivatives bearing structurally diverse alkyl promoieties and evaluated their hydrolytic stability, anticancer activity, and drug-like properties through experimental and in silico analyses. Antiproliferative activity was assessed across a diverse panel of human and murine cancer models, including colorectal (HCT-116, HT-29), lung (A549), breast (MDA-MB-231), and melanoma (B16F10) cell lines. All derivatives underwent rapid hydrolysis under an organics rich autohydrolysis assay, efficiently regenerating niclosamide. While alkyl substitution produced modest differences in hydrolytic stability, these variations did not substantially influence anticancer activity, with the prodrugs displaying comparable potency profiles across the evaluated cancer models. In silico pharmacokinetic and drug metabolism analyses further suggested that prodrug derivatization may offer opportunities to modulate developability while preserving pharmacological activity through rapid bioactivation. Collectively, these findings establish ester and carbonate derivatization as a viable therapeutic delivery strategy for niclosamide and provide a framework for the continued development of niclosamide-based cancer therapeutics with improved pharmaceutical properties and retained anticancer efficacy.