Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition

Michael V. Gormally, Thomas S. Dexheimer, Giovanni Marsico, Deborah A. Sanders, Christopher Lowe, Dijana Matak-Vinković, Sam Michael, Ajit Jadhav, Ganesha Rai, David J. Maloney, Anton Simeonov and Shankar Balasubramanian ()
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Michael V. Gormally: University Chemical Laboratory, University of Cambridge
Thomas S. Dexheimer: National Center for Advancing Translational Sciences, NIH
Giovanni Marsico: Cancer Research UK, Li Ka Shing Centre, Cambridge Institute
Deborah A. Sanders: Cancer Research UK, Li Ka Shing Centre, Cambridge Institute
Christopher Lowe: University Chemical Laboratory, University of Cambridge
Dijana Matak-Vinković: University Chemical Laboratory, University of Cambridge
Sam Michael: National Center for Advancing Translational Sciences, NIH
Ajit Jadhav: National Center for Advancing Translational Sciences, NIH
Ganesha Rai: National Center for Advancing Translational Sciences, NIH
David J. Maloney: National Center for Advancing Translational Sciences, NIH
Anton Simeonov: National Center for Advancing Translational Sciences, NIH
Shankar Balasubramanian: University Chemical Laboratory, University of Cambridge

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6165

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