Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition

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 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.

FOXM1 is a critical driver of lung fibroblast activation and fibrogenesis

“…Optimal dosing and route of administration remain to be defined. Furthermore, a number of classes of small molecule inhibitors of FOXM1 are currently under development (61,62), and these may be more attractive therapeutic candidates for treatment of fibrotic lung disease than is Sio A.…”

FOXM1 is a therapeutic target for high-risk multiple myeloma

“…Further encouraged by new evidence indicating that FOXM1 (1) drives tumor development and progression 15–19 by virtue of a complex mechanism that includes enhanced cell proliferation, migration and invasion 6 , regulation of the DNA damage response 20 and changes in the cancer epigenome 21 , (2) promotes cancer-cell resistance to ionizing radiation 22 and cytotoxic drugs 23 , (3) governs, in part, the survival and tissue-regenerating capacity of both normal hematopoietic stem cells 24 and malignant stem cell-like cells 25 , (4) links acquired resistance to cancer therapy with cancer stemness 26 and (5) owing to the development of specific small-molecule inhibitors 27 , may soon be targeted more effectively than possible in the past 28 , we here decided to evaluate whether FOXM1 might play an important but heretofore overlooked role in plasma cell myeloma.…”

Fox transcription factors: from development to disease

“…However, these drugs are also associated with serious side effects (Adams et al, 1999), so more specific inhibitors of FOXM1 have been sought. Recently, a high-throughput screen identified a small molecule, FDI-6, that makes direct contact with the DNA-binding domain of FOXM1, blocks the interactions of FOXM1 with its transcriptional targets, and suppresses the expression of those targets (Gormally et al, 2014). FDI-6 is specific enough that it does not affect the binding or function of other Fox transcription factors, and it also does not affect proteasomal activity.…”