Just a short note today – I know that a lot of readers in the Northeast will be snowed out of work today anyway, but there are plenty of others who aren’t! I wanted to mention this short review on targeted protein degradation in J. Med. Chem. (a subject I last wrote about here). It’s a very readable intro to the field, and gets across its promises, uncertainties, and complications. These are still early days, but everyone’s piling into this area (as witness today’s news of the Pfizer/Arvinas deal).
A lot of things have to go right for this technique to work, but the exciting part is that it works as often and as well as it does already. That would have to make you think that as we get a better handle on the various factors that we’ll have even more success in this area, which would give us the ability to target disease in ways that are currently impossible. Those impossibilities come in several forms. You could hit proteins for which we have no real small-molecule inhibitors (since for TPD you just need to find a binder, not necessarily something functional). The downstream effects of protein degradation are also quite different from pharmacological inhibition, as you’d imagine, since you’re yanking all the other protein-protein interactions up by the roots, and that’s also something that’s not been possible to do in this fashion.
The tricky part, though, is that you do need a binder, and there are plenty of interesting proteins for which no believable small molecule binders have been found. My guess (and my hope) is that this situation obtains because so many assays have had functional readouts, rather than just binding-event readouts, and that as we concentrate more on the latter we’ll find more hits that can be turned into degradation “warheads”. But we’ll see about that.