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Suppression of the FOXM1 Transcriptional Programme via Novel Small Molecule Inhibition

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, Shankar Balasubramanian

Nat Commun. 2014 Nov 12;5:5165.

PMID: 25387393

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP313380277	FDI-6		313380-27-7	Price

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