I’ve mentioned it in passing before, but it bears repeating: this is a really unusual moment in drug discovery. We have simultaneously more new modes of action for therapy coming on in the clinic than I can ever recall, and some older ones are getting reworked to join the action. This short overview is a good look at the topic. Things that many of these have in common are new interfaces between small molecule organic chemistry and biomolecules. We still have a lot of enzyme inhibitors and receptor antagonist drugs out there, but these classic mechanisms (which, you will note, depend mainly on our ability to gum up the works in the right spots) are being joined by protein degradation, gene therapy (CRISPR and others), exon skipping, attempts to go after various RNA species, more non-active-site targeting of proteins, a new wave of antibody-drug conjugates, and more.
One way to look at these things is as a triumph of what we now call chemical biology. I have a slide deck that makes the assertion that chem-bio is the way forward in general, so I’m already biased toward that idea (and the fact that I work in a department focused on that stuff has something to do with it, too). But I think there’s a good case that the tools of that field, and the mindset behind it, are important factors. There are a lot more cellular processes that we can imagine targeting than we ever have actually been willing or able to.
To be sure, some of these represent yet more ways to gum up the works. But I think that drug discovery has always been biased in that direction, because we’re inside cells that have had a billion or two years to work out some very slick processes and tune them up to concert pitch. Stepping in and making these perform even better is a real challenge, whereas throwing a spanner wrench into the gears is much more feasible. That has tended to make the central problem of drug discovery “What process should we beneficially shut down?” This accounts for the number of bounce-shot double-negative mechanisms that you see in this business: what we want to do is activate Pathway X, but the way that we might manage to do it is to inactivate some inactivating mechanism (kinase Y or protease Z) and thus set it free. Drug development, often enough, consists of fashioning just the right size and shape of spanner wrench and flinging it just so into the bewildering mass of cellular machinery in order to bring a particular set of gears to a grinding, screeching halt.
Gene therapy is the outlier of that bunch – it doesn’t work through a small molecule agent, and it is generally aimed at directly restoring function. What it shares with the others, though, is a great deal of what can only be called novelty. We really don’t know what’s going to happen when we step in and try to rewrite some little strech of a patient’s genome, in the same way that we don’t know what’s going to happen when we give them a bifunctional molecule that targets some particular protein for degradation. People haven’t had these things done to them before. And if there’s one thing for sure in this work, it’s that we don’t know a lot of the pathways and connections out there in the cells yet. Doing things to human cells (and to human patients) that you’ve never tried before is a way to uncover some of those, and experience has shown that not all the things you uncover are good.
That’s a roundabout way of saying that I hope that these new therapeutic modes actually make it through. Having so many new mechanisms under development at the same time increases the chances that something unexpected and unwelcome will happen. That post the other day on idiosyncratic toxicity is an example, and that’s just one of many possibilities. Some of those we have seen before (but can’t anticipate accurately) and some of them are things that we will be learning about for the first time.
That’s most certainly not an argument to slow down or steer clear; it’s the cost of doing business in early-stage drug research. And there are worse problems than having a lot of new, interesting, and exciting stuff hitting more or less all at once. But I will be very glad to see more degraders, CRISPR attempts, RNA mechanisms and so on make it further into human trials without anything weird happening. We need these new shots on goal, and I hope that we can take then as cleanly as possible. This is a big moment – let’s hope it continues.