Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition.
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.
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.
Michael V
MV
Gormally
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland 20850, USA.
Thomas S
TS
Dexheimer
Cancer Research UK, Li Ka Shing Centre, Cambridge Institute, Cambridge CB2 0RE, UK.
Giovanni
G
Marsico
Cancer Research UK, Li Ka Shing Centre, Cambridge Institute, Cambridge CB2 0RE, UK.
Deborah A
DA
Sanders
University Chemical Laboratory, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Christopher
C
Lowe
University Chemical Laboratory, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Dijana
D
Matak-Vinković
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland 20850, USA.
Sam
S
Michael
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland 20850, USA.
Ajit
A
Jadhav
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland 20850, USA.
Ganesha
G
Rai
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland 20850, USA.
David J
DJ
Maloney
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland 20850, USA.
Anton
A
Simeonov
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.
Shankar
S
Balasubramanian
D015153:Blotting, Western; D002843:Chromatin / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005454:Fluorescence Polarization; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors*; D057166:High-Throughput Screening Assays; D006801:Humans; D061986:MCF-7 Cells / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D002843:Chromatin; C000603299:FDI-6 compound; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D011725:Pyridines; D013876:Thiophenes