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

Abstract

Background Transcription factor FOXM1 is a potential target for anti-cancer drug development. An interfering peptide M1-21, targeting FOXM1 and FOXM1-interacting proteins, is developed and its anti-cancer efficacy is evaluated. Methods FOXM1 C-terminus-binding peptides are screened by in silico protocols from the peptide library of FOXM1 (1-138aa) and confirmed by cellular experiments. The selected peptide is synthesized into its D-retro-inverso (DRI) form by fusing a TAT cell-penetrating sequence. Anti-cancer activities are evaluated in vitro and in vivo with tumor-grafted nude mice, spontaneous breast cancer mice, and wild-type metastasis-tracing mice. Anti-cancer mechanisms are analyzed. Distribution and safety profiles in mice are evaluated. Results With improved stability and cell inhibitory activity compared to the parent peptide, M1-21 binds to multiple regions of FOXM1 and interferes with protein-protein interactions between FOXM1 and its various known partner proteins, including PLK1, LIN9 and B-MYB of the MuvB complex, and β-catenin. Consequently, M1-21 inhibits FOXM1-related transcriptional activities and FOXM1-mediated nuclear importation of β-catenin and β-catenin transcriptional activities. M1-21 inhibits multiple types of cancer (20 µM in vitro or 30 mg/kg in vivo) by preventing proliferation, migration, and WNT signaling. Distribution and safety profiles of M1-21 are favorable (broad distribution and > 15 h stability in mice) and the tested non-severely toxic dose reaches 200 mg/kg in mice. M1-21 also has low hemolytic toxicity and immunogenicity in mice. Conclusions M1-21 is a promising interfering peptide targeting FOXM1 for the development of anti-cancer drugs.

MFPPDB: a comprehensive multi-functional plant peptide database

“…Since the introduction of insulin therapy in the last century, peptide therapies have also been used in medical treatment in recent years, and dozens of peptide drugs have been approved to enter the market ( Muttenthaler et al., 2021 ). For example, the peptides for oral use ( Kong et al., 2020 ), a long-acting glucagon-like peptide-1 in healthy male subjects ( Elbrønd et al., 2002 ), an anti-cancer peptide targeting the transcription factor FOXM1 ( Cheng et al., 2023 ), the cyclic peptide drugs ( Zhang and Chen, 2021 ), peptide Etelcalcetide indicated for secondary hyperparathyroidism ( Hamano et al., 2017 ). Therapeutic peptides have been used to treat various diseases such as cancer, diabetes, HIV, and cardiovascular diseases ( Wang et al., 2022 ).…”