A traditionally "undruggable" site was thought to be protein-protein interaction surfaces. In this context, there has been tremendous progress made for example in disrupting nuclear receptor-coregulatior interactions. This also tells us that besides ligand binding pockets there are many pockets on TFs that could bind ligands, which perhaps would eventually break our classical understanding of ligand-binding domains etc.. . Similarly, TF-DNA binding has perhaps similar properties and that the notion that a DNA binding domain might be necessary for oligo binding may eventually undergo a similar fate. Thus it seems certain that all these pockets are "druggable". The key is reduction of off-target effects and toxicity.

Transcription factors bind DNA so why can't we target the DNA binding surface? If we make a sequence logo from proven (!) binding sites, we can have a pretty good idea of what contacts are made and of course X-ray crystal structures nail it down. One could imagine a double stranded PNA with (perhaps) a crosslinker that targets a particular factor. Getting that large molecule into cells might be a problem though.

I would not say that we lack the means to inhibit proteins that are not enzymes; we do quite well finding antagonists for cell surface receptors, for example. But it is true that transcription factors have proven notably refractory to specific inhibition, and I think it may be worthwhile to think carefully about why that is so. I do like the topic, because I think the tools to address this problem are in our hands now, and the payoff would certainly be big. I'm glad the term "undruggable" was put in quotes, because if recent history teaches us anything, it should be that there is probably no such thing as an undruggable target.