Podcast: The small-molecule drug renaissance

As the science of drug discovery has grown in scale and gotten more complicated, so have the drug molecules themselves. But there’s a promising class of drugs made of just a handful of atoms that punch above their weight by leveraging the natural chemistry of the cell.

Recent discoveries have opened up a new era of pharmaceutical chemistry that some people are calling a golden age. In this episode of C&EN Uncovered, reporter Laura Howes explains this exciting field of research and its implications for the drugs of the future.

C&EN Uncovered, a project from C&EN’s podcast,Stereo Chemistry, offers a deeper look at subjects from recent stories. Check out Laura’s cover story on small-molecule drugs at cenm.ag/smallmol.

Subscribe toStereo Chemistry now on Apple Podcasts, Spotify, or wherever you listen to podcasts.

Credits

Executive producer: Gina Vitale

Host: Craig Bettenhausen

Reporter: Laura Howes

Audio editor: Brian Gutierrez

Copyeditor: Bran Vickers

Story editor: Mitch Jacoby

Episode artwork: Chris Gash

Music: “Hot Chocolate,” by Aves

Contact Stereo Chemistry: Contact us on social media at @cenmag or email cenfeedback@acs.org.

The following is a transcript of the episode. Interviews have been edited for length and clarity.

Craig Bettenhausen: Welcome to C&EN Uncovered. I’m Craig Bettenhausen. C&EN Uncovered is a podcast series from Stereochemistry. In each episode, we’ll take another look at a recent cover story inChemical & Engineering News and hear from C&EN reporters about striking moments from their reporting, their biggest takeaways, and what got left on the cutting-room floor.

In this episode, we’re talking about a recent cover story about small-molecule medicines, which appeared in the Oct. 30th issue of C&EN. We’ll put a link in the show notes. I’m here with C&EN’s executive editor for life sciences, Laura Howes, who wrote that article. Hi, Laura.

Laura Howes: Hi, Craig.

Craig: For anyone that hasn’t had a chance to read your story yet, can you give a brief recap of what’s in the article?

Laura: OK. So, I think the main takeaway from the article is it’s a little bit of a kind of almost “state of the union” of drug discovery options for medicinal chemists. And more importantly, a kind of an argument that even though a lot of people get excited about new, whizzy biological modalities—whether that’s antibodies or the new CRISPR therapeutics that have just started to be approved—there’s a lot of life still in what we call small-molecule drugs.

Craig: All right, so, let’s get into the meat of it a bit. What makes a drug a small molecule?

Laura: Oh, that’s a great question, and it’s one that has been debated, and still is debated, and is continually changing. So, I would say for me personally, and this is really personal, is that it’s a small-molecule drug if I can sit down with a pen and paper and draw the structure of that drug.

I’m not the greatest chemist; I’m not going to be, you know, fantastic at drawing these things. But compared to, say, trying to draw out CRISPR-Cas9 machinery to edit what’s going on and in someone’s DNA, that’s just not going to happen.

There are some characteristics that small-molecule drugs have. They do tend to be not just smaller, but they tend to be more likely to be what we call orally bioavailable. So that means that you can take it as a pill or as a suspension, or something like that, rather than needing to have an injection in a hospital or something.

So, if you think about the drugs that you are taking day to day, maybe you get strep and you need an antibiotic, that’s a small molecule. If you have had COVID and been prescribed Paxlovid, like the antiviral, that again is a small-molecule drug.

Craig: So, it sounds like small molecules are kind of most of the day-to-day drugs, is that a right way to think about it?

Laura: I think historically that’s definitely been one of the ways that people have thought about it. The workhorses of most of pharmaceuticals are small molecules. But I would say that there has been innovation.

So, Craig, inside your body, there’s about 20,000 different proteins—lots of copies of them, but about 20,000 of them. I think we currently drug a very, very small percentage of that, like maybe 600, 700 of those proteins.

So, there’s a lot of space to play. The turning point, I think, is that we have often thought that a lot of these proteins were what was called undruggable, that there was nothing to really grab onto to effect a change. And what we’re seeing is that that’s starting to change.

Craig: And how did the story come to be? What attracted you to the topic?

Laura: Just from things that I and other reporters were hearing, that this was a golden age of small-molecule drug discovery, and so I guess the question really was, “Well, is it?”

And if it is, what does that mean?

Craig: So, I think a small molecule that binds a protein sounds cool, but as you said, the body has a ton of different proteins. How are these things targeted?

Laura: So, historically, there’ve been a few different ways of these drugs going after proteins. And when I was a student, I was learning about what we called the lock-and-key mechanism, which was really about going into a protein, finding some kind of site that was really important, and blocking it.So you were just like stopping the protein from working because you’d blocked it with some kind of chemistry.

What we’re seeing now is different ways that maybe it’s not that we’re blocking and stopping that protein from working, but maybe we’re modifying that protein, or changing its activity, or changing how it binds to other proteins and how it’s interacting with other biology within the cells. And that’s a very different way of thinking about things.

Craig: So, yeah, I mean, I guess I think of even something like caffeine, because that’s blocking the active site of the protein. But this is a new sort of paradigm.

Laura: This is a new paradigm, absolutely. And I think one of the major driving forces of this new excitement is what people will call either targeted-degradation or induced-proximity drugs.

These are different ways of trying to bring different proteins together to hang out and then do something that they would maybe be doing anyway, but kind of force it to do more of it or do less of it, and modify things that way.

Craig: Yeah, I want to dig into this induced-proximity thing because I found it both interesting and confusing at the same time. So, one of the big molecule classes in your story is these PROTACs. What is a PROTAC?

Laura: OK. So, PROTACs are proteolysis-targeting chimeras, which is a kind of complicated name. But what you really need to understand about that is that PROTACs have a unique structure. Think of it as having a wiggly linker. On either end of that wiggly chemical linker, there’s something sticky that’s going to stick to a protein.

And what the PROTACs help do is pull together a protein that’s disease causing, that it’s kind of grabbed hold of, and the machinery that helps add on these tags to say, “Let’s get rid of this.” And it’s those tags that then get taken by some more complicated machinery and start pulling those proteins apart and putting them into the garbage disposal.

Craig: How do these proteins cause diseases? What went wrong with them?

Laura: Well, the classic example is definitely cancer, and tumors, where you’ve got a mutated version of a protein. And that’s causing problems in your body, and if you can get rid of that protein, maybe you kill the cancer. But also maybe there’s just too much of this protein. It exists. It’s useful, but there’s too much of it.

Craig: And how does the PROTAC know which protein it should stick on to?

Laura: Well, that’s the magic of chemistry. So, that’s all about making sure that the sticky bit is designed specifically for the protein that it wants to stick on to—that you want it to go after. And that is all chemistry, so that’s all going to be about energy surfaces and fine-tuning of the bonds between the sticky end of your PROTAC and the protein.

Craig: So, where did these PROTACs come from? How did we stumble on these things?

Laura: So, PROTACs have probably about just over a 20-year history. And they came out of academics being interested in that protein destruction process. So, how are cells looking after proteins? How are they modifying them?

If you think about a virus invading your cells, for example, they’re trying to modify those cells to their own ends. HPV [human papillomavirus], for example, which is the herpes-causing virus. And there are plants that have small molecules that can induce this kind of pathway. Once you start thinking, “Oh, we’re going to explore the biology and understand what’s going on.” OK, if viruses and plants are able to do this, can we do this as chemists?

And one of the key people involved there was Craig Crews at Yale. He and his team and collaborators really went looking to see if they could design something that could do the same thing that they’d noticed in nature.

He published a paper in 2001 with the very first what we would now call PROTAC, and I think he does use the term in that paper. And it was around 2019 that the first PROTACs then went into human trials.

Eighteen-ish years later, those trials have shown that indeed these drugs are drugs, that they do what we would want them to do. For one, they’re safe. And that they have a therapeutic effect.

Craig: So, among the PROTACs that are in the pipeline for, you know, approval as drugs, what kinds of diseases do they treat?

Laura: So, for the ones that are in kind of, you know, later-stage clinical trials, very often they’re different types of cancers. So, especially prostate cancer, breast cancer. Also some autoimmune diseases. But predominantly cancers and things like that, where you’ve got a very clear, here is a mutated protein that is causing a problem. We can go after this mutated protein and get rid of it, and therefore kill the tumor cell, the cancer cell.

Craig: Sure. How big of a deal was the discovery of PROTACS?

Laura: When those papers came out, a lot of people got very excited and started putting money and effort in. But I think there was still some skepticism for a while: “OK, this is going to work in the lab, but is it going to work in a patient? Is this going to go anywhere?”

And I think those naysayers have definitely been proved wrong over time. And that’s also then shown in the other related drugs that you are seeing people start to design.

So, we have a raft of acronyms, and I am not going to use them all, but they start to describe different chimeric options for targeting not just proteins for degradation but, for example, RNA for degradation. So, that’s RIBOTACs [ribonuclease-targeting chimeras]. There are also LYTACs [lysosome-targeting chimeras], which are going after extracellular proteins much more. And others as well.

And then there are also people who are working on other induced-proximity drugs. So, whereas we’ve been talking the whole way through about taking a protein and marking it for disposal, maybe you could take a protein and grab a different enzyme within the cell and mark it to be kept, for example.

So, this is where we’re kind of going with these, which shows that there’s ways that you can use chemistry to affect and modify the biology going on in a cell. It’s fascinating to see the different ways that people are using chemistry to design new drugs, and go after new targets, and think about treating disease.

Craig: Are any of these being used in people today, like being prescribed?

Laura: Oh, not yet. So, great question, but no, we’re still very much in the clinical trial stage of this. We’ve definitely got data that it’s looking good. And I definitely think that people say it’s a “when” these things are going to be approved, not an “if,” but right now there’s nothing actually on the market.

Craig: You mentioned in your story molecular glues, which have a similar mechanism in that they’re making multiple proteins stick together. What’s the difference between a molecular glue and a PROTAC?

Laura: So, if you think about PROTACs, what they have is two sticky ends and a kind of flexible linker. And they’re grabbing one thing and grabbing the other, and they get close together, and that’s how it happens. Glues are really much smaller than that, and they just kind of like glom on to both of the proteins involved.

So, rather than having a kind of wiggly linker and two sticky ends, it’s really about making it so that those two proteins will come together happily, but with a much smaller molecule.

And it’s interesting because I think molecular glues are in some ways a kind of later development, but there were already drugs that were molecular glues that we just didn’t know, when they were first approved by the FDA, that that’s the way that they were working.

And one of the classics for that is thalidomide—which obviously then it turned out there were quite a lot of problems associated with thalidomide. But the actual mechanism of action is as a molecular glue, and thalidomide is now being used for other treatments, just not in pregnant people who, you know, have morning sickness, which was the original treatment.

Craig: Yeah, it’s probably a whole other podcast episode, but the idea that we don’t necessarily know as much maybe about the mechanisms of the drugs that are approved as we think, like the FDA is kind of efficacy based in their approvals, if I’m not mistaken, and the other regulatory bodies too.

Laura: Yeah. So, when people are approving drugs—the FDA, the European Medicines Authority as well—they’re really looking for “Is it safe?” and “Is it giving you a good enough improvement?”

You don’t actually have to know how the drug works. We’d all like to. But you don’t have to know how it works; you need to know that it works.

Craig: How is small-molecule drug discovery different from the other ways you find drugs?

Laura: Oh, well, I think there’s a lot of similarities, right? You’re going to be looking for a disease. If you talk to pretty much anyone in pharmaceuticals, there’s a wish list of like, “These are the proteins we wish we could drug, and we’re going to try and go after them.”

But I think that there have been some technological advances that have helped, especially with small-molecule drug discovery. And especially around the idea of what we call proteomic screening. So, this is really trying to mix up small drugs and proteins, and then look at them as a mix with a mass spectrometer, but pull them apart and see what has been modified.

So, if you’re looking for the starting point for a drug, you’re not going to build everything complicated in one go and be like, “Is this my drug?” What you’re going to do is be like, “OK, let’s get a load of smaller pieces of, you know, what could become a drug, and test that.” And then iterate. And then build.

And how exactly you manage those tests, those assays, how exactly you manage those libraries of these compounds—that might vary, there’s different ways of, of managing those, but it’s really about having a lot of diversity in your chemistry so that you can try a lot of things and then iterate based on what hits.

Craig: So, you might have totally different chemistries getting hits in one of your many well plates. And you would make a hybrid molecule that has a couple of different of those molecular groups.

Laura: I think that’s definitely kind of the idea, or what you get as a hit might tell you in what direction you want to be building your molecule, right? Or it might tell you that there’s actually an area of the protein that you weren’t even aware of that is accessible to be bound—because proteins are wobbly, and they move, and they flap open and closed—if a molecule can get in there, even if you don’t see it. So, it might give you an idea of where there’s a toehold or somewhere that you might want to go.

I think the other things that have made this really possible now are the computational power that we now have. So, the way that people can model these molecules but also just deal with the huge amounts of data that they’re producing, and share it, and modify it. I don’t think there’s a pharmaceutical firm on the planet that isn’t investing in the buzzwords of artificial intelligence and machine learning, but that’s because they will have a lot of data. Because that’s what they have to do: they have to create a lot of data to go looking for these new drugs. And so I think that that has also really enabled this.

There are also some, you know, some other cool chemistries. We cover a lot about skeletal editing. So, this is able to make single swaps for molecules.

Craig: Skeletal editing. That’s like when you can, you know, in a ring, swap out a targeted carbon for a nitrogen and things like that, right? That’s the same?

Laura: Yeah, that’s exactly—

Craig: That’s wild.

Laura: That’s exactly right, and, like, that is completely wild.

Craig: So, drug discovery is of course a huge field, and a lot of our audience works in drug discovery. Were there topics and tangents you explored when reporting that didn’t make it into the final story?

Laura: For the beginning of the drug industry—if we’re talking like 120 or so years ago—people were doing what we would call now phenotypic screening. So, that’s chucking something at a person and seeing if it changed their disease.

Craig: Phenotype is kind of the symptom-level way of looking at it, right?

Laura: Absolutely. A lot of what we’ve been talking about has really been trying to design things to go after a specific protein: “Can I get into this protein? Can I inhibit this protein? Can I do something to what this protein is doing?”

But I think, especially with the idea of repurposing drugs, there are people who are now going back to that almost phenotypic way of thinking about it.

So, if you’re looking at—somebody has very rare disease, and you’re just trying to find something that can modify it, then maybe the best way of doing it is to build a model—whether that’s a model in a cell or a model in a mouse—and test a whole run of drugs against that model and see if something sticks.

But I think we’re going to be seeing more of that. Especially for populations and groups with very rare disorders, where they’re really looking for anything that can help them. Then it’s incredibly helpful if we can just go back and say, “Well, there’s this drug, which maybe is off patent, or maybe this drug has been superseded by a later edition, but it’s still, it’s still good, and it’s still available, and it can also maybe treat this disease.”

Craig: So, part of the story you said was inspired by kind of hearing people tossing around the term “golden age,” and whether or not we’re in one. After your reporting, what’s the verdict?

Laura: We’re not saying “golden age.”

Craig: OK.

Laura: “New age,” “renaissance”—I think those are more the terms. “Golden age” implies that it’s the best time ever and, you know, there have been some incredible feats of chemistry in drug discovery before. But I think this is really a new and exciting time, and I think that’s what people were trying to get across. There’s a lot that can be done, and that’s a lot that’s getting people really excited about what can be done, again with small molecules, and it’s going to result in some really cool drugs.

Craig: Laura, thanks for introducing us to the renaissance of small-molecule drugs.

Laura: I’m happy that we got to do this, Craig, so thanks very much for coming on the line and talking to me.

Craig: So, for listeners, you can find me on social media as @CraigofWaffles. Laura, how can they find you?

Laura: So, I’m on at least some of the social medias as L-underscore-Howes, H-o-w-e-s, and if not, then C&EN has a website, and you can find me there, and that has my email address.

Craig: So, you can find Laura’s cover story about small-molecule drugs on C&EN’s website or in the Oct. 30th print issue of C&EN. We put a link in the show notes along with the episode credits.

We’d love to know what you think of C&EN Uncovered. You can share your feedback with us by emailing cenfeedback@acs.org. This has been C&EN Uncovered, a series from C&EN’s Stereo Chemistry. Stereo Chemistry is the official podcast of Chemical & Engineering News.

Chemical & Engineering News is an independent news outlet published by the American Chemical Society. Thanks for listening.