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Med-Chem Should Be Larger Than It Is

I’m really glad to see this Perspective article in the Journal of Medicinal Chemistry, not least because it hits on a theme that I emphasize whenever I get a chance to speak to graduate student chemistry audiences. The author, Bart Roman, is pointing out that (1) biologics are relentlessly expanding their role in the landscape of approved drugs and (2) this means that organic and medicinal chemists have a new area to work in.

Not all of them have thought that way over the years, for sure. Many of these biologic agents (monoclonal antibodies, to pick a big class of them) are aimed at targets that are very difficult to affect with traditional small molecules. The natural tendency has been to leave the antibody folks to it and assume that this area is outside the purview of synthetic organic chemistry. After all, antibodies aren’t discovered or produced by traditional chemical technologies, and they have rather different behavior once dosed in animal models or patients. And they’re usually developed by completely different parts of an organization, assuming that the company even does small-molecule drug discovery and antibodies at the same time.

But as Roman says, “Small molecules are no longer the rule, and biologics (are) no longer the exception“. Medicinal chemists shouldn’t step aside for biologics or try to pretend that they aren’t there. Instead, we should be trying to claim some of this territory as our own, using the specific skills that we can bring to the process. This could have the desired effects of making both biologic drugs and medicinal chemists simultaneously more valuable.

The article specifically mentions working on late-stage protein modification techniques and post-translational modifications in general, and that seems like a sound plan. Modifying the plain amino acid sequence of a given protein is most easily done through molecular biology, but adding non-amino-acid tags are another thing entirely. It becomes harder and harder to use biological methods for those as they get more exotic (non-natural amino acids, genetic code expansions, and so on), which provides a real opportunity for chemical synthesis to step in. More and more of this sort of work has appeared in recent years, and there are a lot of opportunities yet to be realized. In the same way that late-stage functionalization of “regular” synthetic molecules or natural products has been increasingly employed, being able to modify proteins after they’re already made is a goal worth reaching for.

What does that get you? An obvious application is making tools for chemical biology (fluorescent tags and other markers), but you can also make real therapeutics. Antibody-drug conjugates, for example, have been around for quite a while now, but they seem to be undergoing an upsurge. The hot field of bifunctional molecules (targeted protein degradation is just the beginning) also can surely expand into protein-small molecule hybrids. There are clearly a lot of things yet to be discovered in these area, and we’re going to need better and easier ways to make protein-small molecule conjugates in order to explore that huge space.

Freeman Dyson famously argued that scientific fields go through periods were they’re driven forward by new ideas and through periods when they’re driven by the availability of new tools that allow experiment that couldn’t be performed before. The merger of synthetic organic chemistry and molecular biology is ready, I’d say, for the latter. If every new modified protein is a whole project in itself, a lot of experiments just don’t get tried, and we don’t learn as much. But if there are a variety of reasonably good ways to make such things, we can explore all sorts of hypotheses as they come up, or just turn out libraries of them and see what happens.

The larger point is that medicinal chemists need to avoid the temptation to bemoan their fate as the world changes around them. Instead, we should be looking for new territories to explore, new places to make our own. Synthetic organic chemistry (to put it mildly) is not a widely distributed skill set – nobody else is going to do these things, or certainly not as well as the organic chemists can. So let’s show how valuable it is!

25 comments on “Med-Chem Should Be Larger Than It Is”

  1. There is at least one company, Bright Peak, using synthetic chemistry to make therapeutic proteins.

  2. Dennis says:

    Yes!! There are so many opportunities for chemists to contribute in all of these areas, and scientists from other fields are eager to work with us. This is an incredibly exciting time for drug discovery. Regardless of whether the focus of our programs are SMI or large/biologic, project teams should always consider all options and try what makes most sense for patients.

    There was a fantastic talk by AbbVie recently on their Bcl-XL program – they went from a small molecule approach to an ADC approach based on projected TI and I believe it was the chemists that advocated for and led the large molecule program.

  3. Gavin Bennett says:

    Been working on this at Bicycle Therapeutics for some years: multiple small molecules now in the clinic, with affinity & selectivity of antibodies.

  4. Cameron Pye says:

    Shameless plug for Unnatural Products Inc., synthetic macrocycles with truly small-molecule-like PK, including passive cell membrane permeability, drugging intracellular “undruggable” targets.

  5. c says:

    If I was speaking to a graduate student chemistry audience group I would encourage them to learn to program. Spending months of your life washing glassware isn’t something that a productive mind in the 21st century should be encouraged to do.

    1. Marcus Theory says:

      I whole-heartedly agree that grad students (well, all students really) should learn computer programming. I also agree washing glassware is a waste of time. But learning synthetic organic skills is far from a waste of time and will continue to be important, as this article (and Derek) highlight. Get your department to buy a dishwasher and keep making molecules!

    2. A computational chemist says:

      Even as a computational chemist, I would say the proper reply to the time wasted washing glass is not to abandon lab work, but to enlist the help of chemical engineers and ask them to build a dishwasher that can wash your nasty glassware with water/acetone/DCM/whatever and dry them while keeping all the waste/fumes contained. Maybe such a thing already exists? I have only seen the kind of lab dishwasher that uses water and special detergents, and I am not sure how well that would work on the more heavily contaminated glassware from an organic lab.

      Sure, we need more hands on keyboards and especially more competent programmers, but please do not abandon your labs.

      1. gippgig says:

        How about developing an open-source build-it-yourself design for one? Is there any systematic effort to develop open-source chem lab equipment?

      2. Dionysius Rex says:

        The solution here is cheap, disposable labware not a $100k superalloy dishwasher that withstands piranha mix.

        1. Charles H says:

          You’re assuming simple glassware. Yes, test tubes are ideally washed by a dishwasher. Anything with a fancy shape, however, is dubious. And anything custom made is dubious. Small diameter glass tubing should just be recycled.

          So, yes, there should be a dishwasher for test tubes and Erlenmeyer flasks, graduated cylinders, etc., but don’t expect it to solve the glassware washing problem.

    3. anon says:

      Grad school has become screening factories, so students don’t wash that much glassware anymore. They simply throw out vials and NMR tubes when they are done. If people say they are spending too much time cleaning glassware, they have poor time management skills.

  6. steve says:

    Coming from an immunologist who works on antibodies and cell/gene therapy: just be aware that it’s not straightforward and that a small molecule drug will beat a biologic every time. Conjugating drugs on to proteins makes them antigenic and may preclude repeat dosing. On the other hand, look at Pfizer’s protease inhibitor PF-07321332. If you had COVID would you rather sit for a few hours at a clinic and be infused with Regeneron’s antibody cocktail or take a pill? Same with Amgen’s kRAS inhibitor – get infused with an ADC or pop a pill? I wouldn’t jump on the bandwagon and shift over to modifying biologics when there is so much that still needs to be done on the small molecule drug side. Each has its own strengths and weaknesses.

  7. Hap says:

    The potential for getting effectively longer patent coverage with biologics rather than the lack of capability of dealing with diseases may be driving the influx to biologics.

    There is likely useful chemistry to be done (anything that helps figure out what your target is and whether it does what you think it does is a good idea, and synthetic modification of peptides can help), but small molecules can do lots of things proteins can’t (or at least are available in ways proteins and peptides may not be), as noted above. I don’t think the jig is up for organic.

    1. sgcox says:

      Indeed.
      There is a perverse insensitive now to focus on expensive and inconvenient biologics instead of orally available small molecules.
      Just look at Humira and compare to Lipitor, Viagra, and zillion other now generic medicines which still make the bulk of prescriptions and its global effect on general human health.
      Until the society finally wake up to the problem, the cost of medicines and the lack of progress in some medical areas will spiral out of control at the expense of potentially more useful medicines which has been effectively de-incentivised now.
      Just IMHO, for what is worth.
      It has been discussed many times here before of course.

      1. Skeptical says:

        @Hap and @sgcox,

        I think you’re both right. Part of the move toward biologics is because of effective patent coverage. Part is because of the difficulty of making biosimilars compared to generic small molecules.

        I think some of the enthusiasm for cell-based cancer therapies is due to the difficulty of creating a true biosimilar for such a complex (and incompletely characterized) product.

        And because of that difficulty, sgcox is right that we’re going to have, at least temporarily, a strong upward push on average drug/therapeutic prices.

        Hopefully some of the new hard-to-copy gene and cell therapies will be curative, which will rebalance the price/effectiveness ratio.

  8. luysii says:

    While it’s not medicinal chemistry, it’s going on inside just about every cell you own right now. It’s a ferociously hard chemical problem because it is inherently nonStoichiometric. I speak of the nonMembranous organelles inside your cells (liquid liquid phase separation if you wish). Organic chemists should start looking at these things.

    No chemist in their right mind would have made them to study. For one thing they contain tens to hundreds of different molecules. Imagine trying to get a grant to see what would happen if you threw that many different RNAs and proteins together in varying concentrations. Physicists have worked for years on phase transitions (but usually with a single molecule — think water). So have chemists — think crystallization.

    Proteins move in and out of these bodies in seconds. Proteins found in them do have low complexity of amino acids (mostly made of only a few of the 20), and unlike enzymes, their sequences are intrinsically disordered, so forget the key and lock and induced fit concepts for enzymes.

    Are they a new form of matter? Is there any limit to how big they can be? Are the pathologic precipitates of neurologic disease (neurofibrillary tangles, senile plaques, Lewy bodies) similar? There certainly are plenty of distinct proteins in the senile plaque, but they don’t look like liquid droplets.

    For more please see — https://luysii.wordpress.com/2020/12/20/neuroscience-can-no-longer-ignore-phase-separation/

    1. Enno says:

      Such a random comment. Anyway, great post as always Derek!

    2. Erik says:

      Good point, the phase transition work in cells is going to be an entire field soon, with multiple conferences and maybe even drug targets getting explored in the next two decades. However, even the low complexity “simple” segments with only four amino acids, 4^45 is around 10^27, which is within an order of magnitude of our current planets total compute power (for a solid year). The current protein energy approximation methods would have to scale to this new class of “phase-related” proteins first, and the DeepMind methods don’t have anything like these in their training data. Lots of interesting work to keep people busy!

  9. bacillus says:

    My former supervisor who worked at the bench into his 80s told me that glass washing allowed him time to think.

    1. home office chemist says:

      food for thought

    2. Hap says:

      In the 10th Periodic Bagel podcast, they talked about the time to think that running columns (and other tasks) can give you. We want people to be doing stuff all the time, but thinking is hard and other tasks require overhead that can’t be used for less-directed thought.

  10. DrOcto says:

    Novo Nordisk has spend years (decades?) trying to get insulin in through the stomach, by synthetic modification of insulin. The result is a very large proportion of their medicinal chemistry team are now all experts in these Frankenstein molecules.

  11. A Nonny Mouse says:

    I make this sort of reactive labels for an academic group at a hospital on a “mate’s rates” basis (otherwise they would not be able to afford it). Maleimides, acetylenes, phosphonics- all the sorts of compounds mentioned in the above review, but this is the first time that I realised what they are for!

    Painful one at the moment that has been going on far too long…..

    Been making lots of stuff for NN as well, so maybe the above project.

  12. anonnymous says:

    @ bacillus……Glass washing to me is more like meditation! And, it is.

  13. Paddy says:

    Cyclic peptides/Macrocycles are making a bit of a comeback. Especially with all the cool screening platforms available.

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