Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition

  • Nat Commun. 2014 Nov 12;5:5165. doi: 10.1038/ncomms6165.
Michael V Gormally  1 ,  Thomas S Dexheimer  2 ,  Giovanni Marsico  3 ,  Deborah A Sanders  3 ,  Christopher Lowe  4 ,  Dijana Matak-Vinković  4 ,  Sam Michael  2 ,  Ajit Jadhav  2 ,  Ganesha Rai  2 ,  David J Maloney  2 ,  Anton Simeonov  2 ,  Shankar Balasubramanian  5
Affiliations
  • 1. 1] University Chemical Laboratory, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK [2] Cancer Research UK, Li Ka Shing Centre, Cambridge Institute, Cambridge CB2 0RE, UK [3] National Center for Advancing Translational Sciences, NIH, Rockville, Maryland 20850, USA.
  • 2. National Center for Advancing Translational Sciences, NIH, Rockville, Maryland 20850, USA.
  • 3. Cancer Research UK, Li Ka Shing Centre, Cambridge Institute, Cambridge CB2 0RE, UK.
  • 4. University Chemical Laboratory, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
  • 5. 1] University Chemical Laboratory, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK [2] Cancer Research UK, Li Ka Shing Centre, Cambridge Institute, Cambridge CB2 0RE, UK.
PMID: 25387393 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.

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