Self-Assembled Peptide PROTAC Prodrugs Targeting FOXM1 for Cancer Therapy.

Abstract

Proteolysis-targeting chimeras (PROTACs) represent a promising strategy for addressing ″undruggable″ proteins in cancer therapy. However, challenges such as poor bioavailability, limited cellular permeability, and inadequate targeting hinder their effectiveness. Herein, we present a novel PROTAC prodrug, NFTP, designed for FOXM1 degradation, which leverages self-assembled peptides functionalized with an integrin α-6 ligand to enhance tumor targeting and proteolysis in vivo. NFTP effectively penetrates tumor cells, induces FOXM1 degradation, inhibits cancer cell survival and migration, and promotes apoptosis in vitro. In a 4T1 mouse xenograft model, NFTP demonstrated efficient FOXM1-targeted degradation, significant tumor growth inhibition, and low systemic toxicity. This self-assembling FOXM1 PROTAC platform demonstrates enhanced tumor-targeting precision and superior therapeutic performance in vivo, representing a promising paradigm shift in targeted cancer therapy.