Transcription factors are a special class of proteins, which allow spatial and temporal control over gene expression. These proteins localize to the nucleus and bind regulatory sites, which mediates the access of RNA polymerase II to the transcription start site. As a result they cause up or down regulated expression of the associated protein.

Progression of disease states is often characterized by abnormal gene expression profiles. As a result, exogenous control of transcription factor-mediated gene expression via small molecule targeting is an attractive goal. Historically, however, successful drug design for transcription factor targets has been limited. Transcription factor surfaces are often hydrophobic and flat, providing for few druggable regions. As direct DNA-protein contacts are made when the DNA binding domains (DBD) of transcription factors associate with enhancers, small molecules that associate with the DBD and disrupt this complexation are promising leads.

Our lab has demonstrated the potential of this approach by examining the FOXM1. This transcription factor is a master regulator of cell cycle progression, which has been implicated in oncogenesis. We have determined that the natural product thiostrepton binds to the FOXM1 DBD, resulting in dissociation of the DNA-transcription factor complex. This work demonstrates the potential druggability of an important regulatory mechanism and paves the way for the rational design of more potent and selective agents that target FOXM1 and other members of the transcription factor family.

References:

A non-canonical DNA structure is a binding motif for the transcription factor SP1 in vitro
E Raiber; R Kranaster; E Lam; M Nikan; S Balasubramanian
Nucleic Acids Research,40 (4), 1499-508 (2012)
DOI: 10.1093/nar/gkr882
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The transcription factor FOXM1 is a cellular target of the natural product thiostrepton
N S Hegde, D A Sanders, R Rodriguez and S Balasubramanian
Nature Chemistry, 3, 725-731 (2011)
DOI: 10.1038/nchem.1114
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