Small-molecule inhibitors of dimeric transcription factors: Antagonism of protein-protein and protein-DNA interactions

Transcription factors are DNA-binding proteins that - usually in combination with other proteins to form the pre-initiation complex (PIC) - regulate the transcription of specific DNA sequences (genes) into mRNA by controlling the recruitment of RNA polymerase II. Constitutive activation of transcription factors can lead to a variety of cancers, and are, therefore, important therapeutic targets. However, in stark contrast to targeting enzyme active sites, disruption of protein-protein or protein-DNA interactions involved in the transcriptional machinery is particularly challenging owing to the large interfacial areas involved, a lack of obvious binding sites and often non-contiguous contact points. Especially problematic for the development of small-molecules is the need by such agents to overcome the large free energy of association between protein-protein and, to a lesser extent, protein-DNA interfaces. Nevertheless, recent years have seen considerable success in this area of medicinal chemistry, cementing the notion that disruption of such interactions is feasible with small-molecule, drug-like compounds. We discuss, in particular, the disruption of dimeric transcription factors, such as STAT3-STAT3, c-Myc-Max and c-Jun-c-Fos (AP-1), with small-molecules that block their protein-protein interactions or their interactions with DNA.