Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition

Nat Commun. 2014 Nov 12;5:5165. doi: 10.1038/ncomms6165.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Blotting, Western
  • Chromatin / metabolism
  • Down-Regulation / drug effects
  • Fluorescence Polarization
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / antagonists & inhibitors*
  • High-Throughput Screening Assays
  • Humans
  • MCF-7 Cells / drug effects
  • Pyridines / pharmacology*
  • Thiophenes / pharmacology*
  • Transcription, Genetic / drug effects

Substances

  • Chromatin
  • FDI-6 compound
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Pyridines
  • Thiophenes

Associated data

  • GEO/GSE58626