Jacob Kimmel

So it's just one example offhand.

Then there are a number of other pathogens, and unfortunately I don't have quite as much molecular detail on some of these, but...

they will interface with other parts of the cell that eventually result in transcription factor translocation to the nucleus and then transcription factors being active.

This actually segues a little bit to your second question on why aren't there more medicines targeting TFs?

In a way, I think many of our medicines

ultimately downstream are leading to changes in TF activity, but we haven't been able to directly target them due to their physical location within cells, and so we go several layers upstream.

If you think about how a cell works in sensing its environment, it has many receptors on the surface, it has the ability to sense mechanical tension and things like this, and ultimately, most of what these signaling pathways lead to is to tell the cell, use some different genes than you're using right now.

That's often what's occurring.

And so that ultimately leads to transcription factors being some of the final effectors in these signaling cascades.

So a lot of the drugs we have that, for instance, inhibit a particular cytokine that might bind a receptor, or they block that receptor directly, or maybe they hit a certain signaling pathway,

Ultimately, the way that they're exerting their effect is then downstream of that signaling pathway, some transcription factor is either being turned on or not turned on, and you're using different genes in the cell.

And so we're kind of taking these like crazy bank shots because we can't hit the TFs directly.

So that sort of begs the question, like, why can't you just go after the TF directly?

Yeah.

Traditionally, we use what are called small molecule drugs where they're defined just by their size.

The reason they have to be small is they need to be small enough to wiggle through the membrane of a cell and get inside.

And then you run into a challenge, which is if you want to actually stick a small molecule between two proteins that have a pretty big interface, meaning like they've got big swaths on the side of them that all, you know, sort of line up and form a synapse with one another, then you would need a big molecule in order to inhibit that.

And it turns out that TF's binding DNA is a pretty darn big surface.

And so small molecules aren't great at disrupting that and certainly even worse at activating it.

So small molecules can get all the way into the nucleus, but they can't do much once they're there.