CDI Exerts Anti-Tumor Effects by Blocking the FoxM1-DNA Interaction

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Forkhead box protein M1 (FoxM1) is a transcription factor overexpressed in most human cancers.
• FoxM1 plays a critical role in cell proliferation, tumor invasion, angiogenesis, and metastasis.
• Targeting FoxM1-DNA interaction presents a promising strategy for anti-cancer drug development.

Purpose of the Study:

• To identify novel small molecules that inhibit the FoxM1-DNA interaction.
• To evaluate the anti-cancer potential of the identified inhibitor in breast cancer cells.

Main Methods:

• Time-resolved fluorescence energy transfer (TR-FRET) assay to screen for FoxM1-DNA interaction inhibitors.
• In vitro assays using recombinant FoxM1-DNA binding domain (FoxM1-DBD) and labeled oligonucleotides.
• Cell-based assays in MDA-MB-231 breast cancer cells to assess proliferation, apoptosis, and gene expression.
• RNA-Seq for global transcript profiling.
• Molecular docking and molecular dynamics (MD) simulations.

Main Results:

• CDI was identified as a potent inhibitor of the FoxM1-DNA interaction.
• CDI suppressed proliferation and induced apoptosis in MDA-MB-231 cells.
• CDI reduced mRNA and protein levels of FoxM1 and its downstream target CDC25b.
• RNA-Seq revealed that CDI decreases the expression of FoxM1-regulated genes.
• Docking and MD simulations suggest CDI binds to the FoxM1-DBD DNA interaction site.

Conclusions:

• CDI is a novel small molecule inhibitor of FoxM1-DNA interaction.
• CDI demonstrates anti-cancer effects in vitro, including reduced proliferation and induced apoptosis.
• CDI's mechanism involves inhibiting FoxM1-DNA binding and downregulating FoxM1-regulated genes.
• CDI holds potential for pharmaceutical applications in developing FoxM1-targeted anti-cancer therapies.