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Description

A cell-permeable thienopyridinylcarboxamide compound that selectively and directly binds to forkhead box M1 (FOXM1) in a 1:1 stoichiometry and reversibly blocks its DNA binding activity (IC50 = 22.5 microM). Does not affect the transcriptional activity of FOXA1, FOXA2, FOXP2, and GATA1 in any significant manner. Shown to suppress the expression of FOXM1 target genes and block the proliferation of FOXM1 expressing breast cancer cells (GI50 = 18 microM for MCF-7 and MDA-MB-231 cells and 21.8 microM for PEO-1 cells). Unlike thiostrepton (Cat. No. 598226), it displays minimal off-target effects and does not affect 20S proteasomal activity., FOXM1 inhibitor FDI-6, NCGC00099374, A cell-permeable thienopyridinylcarboxamide compound that targets forkhead box M1 (FOXM1) winged helix DNA-binding domain (DBD, aa 222-360 in FOXM1c) in a 1:1 stoichiometric ratio and effectively blocking FOXM1 DBD DNA-binding activity (IC50 = 22.5 µ,M by EMSA, 15 nM DNA probe & 750 nM FOXM1 DBD) and displays antiproliferative activity in breast cancer cultures (GI50 = 18 µ,M/MCF-7, 18.1 µ,M/PEO-1, and 21.8 µ,M/MDA-MB-231 with 72 h treatment). FDI-6 culture treatment reduces FOXM1 target genes promoter occupancy (by 36%/CDC25B and 38%/CCNB1 with 6 h treatment at 40 µ,M in MCF-7 cultures) and overall FOXM1 chromatin association (by 43%/20 µ,M and 79%/40 µ,M in MCF-7 cultures), resulting in decreased FOXM1 target genes mRNA level (by 57%/PLK1, 55%/CDC25B, 52%/AURKB, 45%/CARM1 with 6 h treatment at 40 µ,M in MCF-7 cultures). Close to a 19-fold enriched FOXM1 targets is seen among downregulated mRNA species when compared to those not affected by FDI-6 treatment, while little or no enrichment is seen pertaining to targets of highly homologous FOX family transcription factors FOXA1, FOXA2, and FOXP2 among mRNAs affected by FCI-6 treatment. Unlike Thiostrepton (Cat. No. 598226), FDI-6 does not inhibit 20S proteasome activity.