The development of an anti-cancer peptide M1-21 targeting transcription factor FOXM1

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Forkhead box protein M1 (FOXM1) is a key transcription factor implicated in cancer progression.
• Targeting FOXM1 presents a viable strategy for developing novel anti-cancer therapeutics.
• An interfering peptide, M1-21, was designed to target FOXM1 and its associated protein interactions.

Purpose of the Study:

• To evaluate the anti-cancer efficacy and mechanisms of the novel interfering peptide M1-21.
• To assess the stability, distribution, and safety profile of M1-21 in preclinical models.
• To determine the potential of M1-21 as a therapeutic agent against various cancers.

Main Methods:

• In silico screening and cellular validation identified FOXM1 C-terminus-binding peptides.
• The selected peptide was synthesized into a D-retro-inverso (DRI) form with a TAT cell-penetrating sequence.
• In vitro and in vivo anti-cancer activities were assessed in multiple cancer models, alongside mechanism, distribution, and safety analyses.

Main Results:

• M1-21 demonstrated enhanced stability and cell inhibitory activity, binding to FOXM1 and disrupting interactions with key partners like PLK1, LIN9, B-MYB, and β-catenin.
• The peptide effectively inhibited FOXM1 transcriptional activity, nuclear import of β-catenin, and WNT signaling, leading to reduced cancer cell proliferation and migration.
• M1-21 exhibited favorable distribution and stability in mice, with a high non-severely toxic dose and low hemolytic toxicity and immunogenicity.

Conclusions:

• M1-21 is a potent interfering peptide that targets FOXM1 and its associated pathways.
• The study highlights M1-21's significant anti-cancer potential across various cancer types.
• M1-21 represents a promising candidate for further development as an anti-cancer drug.