Suppression of the FOXM1 transcriptional program 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 proliferationand differentiationassociated 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 down-regulation. Global transcript profiling of MCF-7 cells by RNA-seq shows that FDI-6 specifically down regulates FOXM1-activated genes with FOXM1 occupancy confirmed by ChIP-seq. 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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@inproceedings{Gormally2014SuppressionOT, title={Suppression of the FOXM1 transcriptional program via novel small molecule inhibition}, author={Michael V. Gormally and Thomas S. Dexheimer and Giovanni Marsico and Deborah Sanders and Christopher Lowe and Dijana Matak-Vinkovi and Sam Michael and Ajit Jadhav and Ganesha B Rai and David J. Maloney and Anton Simeonov and Shankar Balasubramanian}, year={2014} }