Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• The transcription factor FOXM1 (forkhead box M1) plays a critical role in cell proliferation and differentiation.
• Overexpression of FOXM1 is frequently observed in various human cancers, contributing to oncogenesis and disease progression.
• Targeting FOXM1 presents a promising strategy for cancer therapy.

Purpose of the Study:

• To identify novel small molecules that inhibit FOXM1 activity by blocking its DNA binding.
• To characterize the efficacy and specificity of identified FOXM1 inhibitors.
• To investigate the therapeutic potential of FOXM1 inhibition in cancer cells.

Main Methods:

• High-throughput screening of a library containing 54,211 small molecules.
• Biochemical assays to confirm direct binding of inhibitors to FOXM1 protein.
• Chromatin immunoprecipitation followed by quantitative PCR (ChIP-PCR) to assess FOXM1 occupancy at genomic targets.
• RNA sequencing (RNA-seq) to analyze global transcriptomic changes in response to treatment.

Main Results:

• Identification of novel small molecule inhibitors targeting FOXM1 DNA binding.
• Characterization of FDI-6, a potent inhibitor that binds directly to FOXM1.
• FDI-6 displaces FOXM1 from its genomic targets in MCF-7 breast cancer cells.
• FDI-6 selectively downregulates FOXM1-activated genes, confirmed by RNA-seq and ChIP-PCR.
• The observed effects are specific to FOXM1-controlled genes, with no impact on genes regulated by related forkhead factors.

Conclusions:

• Small molecule inhibitors, such as FDI-6, can effectively block FOXM1-mediated gene transcription.
• FDI-6 demonstrates selectivity for FOXM1-regulated genes, highlighting its potential as a targeted cancer therapeutic.
• Targeting FOXM1 through small molecule inhibition offers a viable strategy for combating cancers characterized by FOXM1 overexpression.