2. Academic Validation
  3. Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-112721
    99.65%, FOXM1 Inhibitor