Self-Assembled Peptide PROTAC Prodrugs Targeting FOXM1 for Cancer Therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Proteolysis-targeting chimeras (PROTACs) offer a new approach for targeting previously "undruggable" cancer proteins.
• Current PROTAC limitations include poor bioavailability, cellular penetration, and tumor targeting.

Purpose of the Study:

• To develop a novel PROTAC prodrug, NFTP, for targeted degradation of FOXM1.
• To enhance tumor targeting and in vivo proteolysis using self-assembling peptides and an integrin α-6 ligand.

Main Methods:

• Design and synthesis of NFTP, a self-assembling peptide PROTAC prodrug.
• In vitro evaluation of NFTP's cellular penetration, FOXM1 degradation, and anti-cancer effects.
• In vivo assessment of NFTP's efficacy and toxicity in a 4T1 mouse xenograft model.

Main Results:

• NFTP demonstrated effective tumor cell penetration and induced significant FOXM1 degradation in vitro.
• NFTP inhibited cancer cell survival, migration, and promoted apoptosis.
• In vivo studies showed efficient FOXM1 degradation, substantial tumor growth inhibition, and minimal systemic toxicity in the 4T1 xenograft model.

Conclusions:

• The self-assembling NFTP PROTAC platform enhances tumor-targeting precision for FOXM1 degradation.
• NFTP exhibits superior in vivo therapeutic performance and low toxicity, representing a promising advancement in targeted cancer therapy.