Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition.

Paradigms and Technologies

Abstract

The transcription factor FOXM1 binds to sequence-specific motifs on DNA (C/TAAACA) through its DNA-binding domain (DBD) and activates proliferation- and differentiation-associated genes. Aberrant overexpression of FOXM1 is a key feature in oncogenesis and progression of many human cancers. Here--from a high-throughput screen applied to a library of 54,211 small molecules--we identify novel small molecule inhibitors of FOXM1 that block DNA binding. One of the identified compounds, FDI-6 (NCGC00099374), is characterized in depth and is shown to bind directly to FOXM1 protein, to displace FOXM1 from genomic targets in MCF-7 breast cancer cells, and induce concomitant transcriptional downregulation. Global transcript profiling of MCF-7 cells by RNA-seq shows that FDI-6 specifically downregulates FOXM1-activated genes with FOXM1 occupancy confirmed by ChIP-PCR. This small molecule-mediated effect is selective for FOXM1-controlled genes with no effect on genes regulated by homologous forkhead family factors.

Authors

Gormally, Michael V; Dexheimer, Thomas S; Marsico, Giovanni; Sanders, Deborah A; Lowe, Christopher; Matak-Vinković, Dijana; Michael, Samuel; Jadhav, Ajit; Rai Bantukallu, Ganesha; Maloney, David J; Simeonov, Anton; Balasubramanian, Shankar;

Keywords

  • Blotting, Western
  • Chromatin/ metabolism
  • Down-Regulation/ drug effects
  • Fluorescence Polarization
  • Forkhead Transcription Factors/ antagonists & inhibitors
  • High-Throughput Screening Assays
  • Humans
  • MCF-7 Cells/ drug effects
  • Pyridines/ pharmacology
  • Thiophenes/ pharmacology
  • Transcription, Genetic/ drug effects

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