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Life in the Drug Labs

How A Real Drug Industry Project Meeting Goes

For those who don’t work in the industry, and wonder what goes on behind the closed doors of the research buildings, allow me to give you a fly-on-the-wall view of a typical meeting of a drug discovery project team. There are no huge revelations here, and I’m not going to try to reproduce 45 minutes worth of talk, but I think that my industrial readers will find this to be a pretty accurate depiction:
(Camera view of the inside of a small conference room, with six or eight people seated around a table)
CHEMIST A: OK, is this everyone that’s going to show up? We have to stop this thing of starting all the meetings fifteen minutes late. (Slide goes up on screen from laptop). All right, here are the two scaffolds, and here’s where we were last time with them. You guys should know that at the last Senior Review Meeting everyone kept asking when we were going to narrow down on just one of these, and I kept having to tell them that we’re not ready to do it yet. But they’re getting tired of hearing that.
CHEMIST B: Not as tired as we are of them asking the question. But I guess you probably didn’t say that? OK, I’ll do Scaffold 1; my lab’s been working on that one the whole time. (New slide goes up). As usual, these things are potent out the wazoo, but we can’t shake that Other Enzyme activity, and none of these compounds have the plasma stability that we want.
Last time we said that we were going to hang a bunch of stuff off the 4-position to try to fix that metabolic problem, but we only got a few of the things made. Every time you try to put anything useful out there, you get this side product, and most of the time you can’t separate the stuff, you can just see it in the NMR and maybe on the LC/MS trace.
But we’ve made these four analogs – the potency isn’t getting any better, but it isn’t getting any worse, and we’ve put ’em in for PK. If they work, though, we’re going to have to find another way to do this stuff.
CHEMIST C: Why don’t you try to put in those groups via (obscure name reaction)?
CHEMIST B: Because (obscure name reaction) doesn’t flippin’ work on this system – we tried that, too, and all we get back is starting material. At least the route we’ve got gives us something. Sometimes. Sort of.
CHEMIST A: What are we going to do if those come back from PK with the same short half-life?
CHEMIST B: Well. . .work on something else, I guess, because if the problem is out here in the 4-position, you’d think that these changes would fix it. Unless we suddenly made some other part of the molecule more likely to be metabolized by messing with this end of it. But you can assume stuff like that all day, and it doesn’t get you anywhere. Keep thinking like that, and you’ll never make anything.
CHEMIST A: OK, we’ll wait for the numbers. My group’s been doing the second scaffold, so I’ll take that one. (New slide goes up). These have always been the most selective compounds we’ve got against That Other Enzyme, and they have pretty good PK numbers, but we keep trying to get more potency. We made this series of amines, trying to pick up a hydrogen bond out there in the far binding pocket, but. . .well, most of them don’t seem to work. They’re really soluble, though. Every time we make something that’s really soluble, it doesn’t bind.
BIOLOGIST A: Yeah, those things were nice. Should have known.
CHEMIST A: The outlier is that third one, the piperazine. That looks like it might be picking up something, so we’re going to make another series off of that one. What we really need is the piperazine with this funky group on it, and you’re supposed to be able to buy it from insert name of fly-by-night supplier, but I don’t want to depend on those guys.
CHEMIST D: So how long are we going to keep beating on these things? Have you guys ever made anything that’s below, like, fifty or a hundred nanomolar?
CHEMIST A: Well, that thiophene compound was the best, and that’s what got us excited, you know, but none of the other aryls seemed to work as well. So we’ve still got the three-position to try out there, and I think we’ve got some intermediates that we can use to get some analogs. I don’t want to pull the plug until we’ve made those. And we need to make that piperazine series that’s up there.
CHEMIST D: But last time you didn’t want to pull the plug until you’d made these compounds. Does the plug ever actually come out, or not?
CHEMIST A: Well, not yet, partly because, hey, when you get down to it, this is probably the best series we have to work on. Nothing else gives us those plasma levels.
CHEMIST B: But there’s only so much that blood levels can do for you if the potency isn’t there. Would you put a hundred nanomolar compound into the animal model?
BIOLOGIST B: I hope not, because as you guys know, that model is a pain in the neck to run, and we’d rather not spend three or four weeks on it unless you’ve got something that you think is going to actually work.
CHEMIST C: What if you try to mimic that right-hand part of the first scaffold with some sort of cyclic amine goes to screen and waves hands like over here? Piperidine, pyrrolidine – would that hit the same part? It looks like there’s space in the X-ray structure to get over there.
CHEMIST A: You want to try it?
CHEMIST C: Well. . .OK. I’ll take a look, see if we can get something like that. You guys have any of the ester left, or did you burn it all up already?
(camera pulls back out of the conference room)
. . .and that’s how it goes. In fact, that’s almost exactly how it goes, most of the time. That’s science as it’s being done.

40 comments on “How A Real Drug Industry Project Meeting Goes”

  1. Mark says:

    “CHEMIST D: But last time you didn’t want to pull the plug until you’d made these compounds. Does the plug ever actually come out, or not?”
    LOL! How true.

  2. Chemjobber says:

    No, isn’t it more like this?:
    Chemist A: Other Company X has come out with this new drug! Great! We’ll just make a me-too!
    Chemist B: ???
    MBA F: Awesome — profit!!!

  3. David says:

    Sorry, but there are some missing participants:
    1. The Project Leader–s/he doesn’t understand the purpose of the meeting but insists on trying to run it
    2. The Marketing Dept Team Member–always asking for a product with no side effects and tremendous potency, wondering why the clinical data isn’t already collected
    3. The Finance Dept Team Member–“What, you want to spend money? How dare you!”
    4. The Project Manager–Only in the pharmaceutical industry do we staff our teams with Project Leaders (who often have PhDs in chemistry or biology and never have had any experience with clinical development or life-cycle management of a drug after it’s approved) and Project Managers (glorified producers of meeting minutes who often are MDs without much understanding of medicine or drug development) to assure that the team is moving forward with its work. Of course, the Project Manager is often so distraught when the team begins missing its deliverables schedule that countless additional team meetings are called to review and discuss why the team is increasingly behind schedule. Time to be concerned: when the meetings get scheduled every twice a day. By then, the meetings last two hours (often with a VP in evidence to berate the team’s lack of performance), and team members need more than two hours to prepare PowerPoint slides detailing what work they couldn’t complete by the time of the next meeting and what would be a “reasonable schedule” for the completion of the required work.
    5. The Clinical Lead–“There’s not enough drug supply.”
    6. Toxicologist–‘This drug looks like the one we did last year which grew cancers in every organ”

  4. MikeEast says:

    What a truly and utterly depressing post. I suppose the last couple of lines suggest that there is actually some colleagiality, critical thinking and goal setting. But if this is the state of medicinal chemistry and drug discovery we’re in a lot of trouble… and this is from a 10-year vet of med chem.

  5. Derek Lowe says:

    You know, I actually didn’t intend for it to be all that depressing. That meeting doesn’t sound like it’s from a project that’s about to recommend something great to the clinic, but that’s the middle of the process, you know.
    My main purpose was more to the point of Chemjobber’s comment in #2 – for the people outside the industry who think that we can just crank drugs out, but (for some reason) don’t. Or that most of the meetings are about what color to make the pills. . .

  6. You're Pfizered says:

    What you forgot to add was not what was actually said, but what was rattling through people’s heads during the meeting:
    Chemist B “Christ almighty, how many more of those inactive compounds are they going to make? They’re just trying to look productive.”
    Chemist C “WTF, that was my idea!”
    Associate Chemist A: “How am I supposed to make enough compounds not to get a bad performance rating based on that crappy chemistry?”
    Biologist B “What the hell is a pyrimidine ring?”
    Director A “What kind of BMW should I buy in the fall when our bonuses come in. 7 series? That new 6 series looks cool.”

  7. milkshake says:

    Often the most important things at project meetings are those that cannot be said aloud: “Why the hell they insist at developing their own functional assay in rats when everybody else uses rabbits and it has been a year already and we still don’t even know if our compounds have any effect in animals”
    and “Why is this dude still working on these ugly series? – Oh, I forgot, since he does not have his own project he was assigned to help us but the only thing he did for the project was busting the prep-HPLC injector and column with his compounds and then he pretended like it was not even his problem.”

  8. DrSnowboard says:

    Not unfamiliar, sadly, but does sound a bit errr… amateur, put down in the interweb like that.

  9. RB Woodweird says:

    Serious Cat is Serious: We have all been in meetings such as this, if not specific to drug discovery. Any organization relying on synthetic chemists has these meetings.
    So what does this common experience tell us about the rapidity or lack thereof with which syntheses can be done? Is it lack of information, lack of time, lack of materials, lack of equipment, or other?

  10. Lucifer says:

    Circular Firing Squad?

  11. InVivo, Veritas says:

    I sit on the biology side of the table.
    My favorite:
    Chemist A: This compound has limited metabolic stability and a poor PK profile, but given the potency, I suggest we run it in vivo. Biology should be fine running the efficacy study with QID dosing, right?
    Biologist A (me): What are you, nuts? Perhaps you can lend me a chemist to come in and handle the midnight & 6AM dosing.
    Chemist A: Why is biology always so obstructionist?!?!
    It would be funnier if it were’nt a true story.

  12. Curious says:

    Chemist A to Chemist B: You know what, some mutagenesis experiments should help us nail down the binding site for that compound
    Chemist B: Management doesn’t “believe” in mutagenesis experiments

  13. FormerMolecModeler says:

    This post is truth.

  14. Wow, fascinating. Thanks for this great perspective. As an outsider looking in, I can’t know for sure if it’s accurate or not, but it was an enjoyable read, nonetheless.

  15. Ty says:

    Sounds more like a chemistry team meeting rather than a project meeting…

  16. lynn says:

    Was Biologist A (who had a cheat sheet for N-containing ring structures). Very accurate portrayal from my point of view. As Derek said, not particularly depressing – because this is a “working” science meeting – at a stage before those other types (marketing, process, project managers, clinical) get involved. Of course, by the time I left Big Pharma, those types got involved earlier and earlier.

  17. drug_hunter says:

    You forgot to add the obligatory riff about how the ligand efficiency is too low and the logP is too high.

  18. HavocDoc says:

    I can relate to this. As indicated, tis a fair rendition of the state of things in mid-discovery phase. There is a target, there are goals for efficacy and the bridge between theory and reality is beginning to take shape.
    I loved the comment regarding Director A. Everyone in the room is tracking how to solve a problem. He tracks how to look good.

  19. anonymous says:

    An X-ray structure? Come-on, man, that’s cheatin’. Try doing it when you really have no friggin’ clue how you are binding the target.

  20. Cellbio says:

    Only vaguely familiar for me, and only to meetings of a decade ago. Much stronger role for the nonchemists in the dialogue now than portrayed above. Operated on the principal that no attribute can be valued as positive without other key positive attributes as well….like the blood levels without potency element of the discussion. We would find it useless to put it in animal models of disease. What would you be probing? Get the molecule right, or put it aside, have a reasonable course to explore SAR, or pull the plug.
    Depressing post IMO. Do agree with the Project Manager venting. Left my last Bigco because it had transitioned to MBA led, metrics driven process BS, where “success” and bonuses are aligned with team determined goals and arbitrary project advancement portals ruled on by VPs whose bonus is also tied to having favorable numbers of advancing projects. All this stemming from the logic that success can be mapped by inverting the failure rate at each stage to arrive at the number of projects needed at each prior stage of development, and multiplying by 10 (for the blockbuster probability). So, it becomess clear, we need 5000 targets screened each year! Ohh, depressing indeed.

  21. Student says:

    Very sorry for hijacking this blog post, but I was reading some total synthesis papers today and they kept mentioning relay compounds. I looked everywhere but could not find a definition so my question is what the heck is a relay compound anyway? Much appreciate if anyone could answer!

  22. Student says:

    Very sorry for hijacking this blog post, but I was reading some total synthesis papers today and they kept mentioning relay compounds. I looked everywhere but could not find a definition so my question is what the heck is a relay compound anyway? Much appreciate if anyone could answer!

  23. Anonymous says:

    Relay Compound is something that you can obtain from the target molecule (natural…isolated one) by some process. This could be one of the penulatimate precursors, and making that intermediate could be painful following 20 steps. So, instead you take the available natural product and chop it down to the precursor. Once you have the substrate in hand, it dosn’t matter as to how was it obtained to develop the conditions for finishing the total synthesis.
    To exemplify, say you have a substrate (penultimate) which just needs carboxylation to get to the final taregt natural product. You do not have enough material, and it is difficult to make it. WHat you do is get the sample of natural product from some vendor, and decarboxylate it and you have the relay compound that can be used to the carboxyl back. These syntheses are of mostly theoritical value as they can not serve the purpose of material supply.

  24. Jose says:

    Just to clarify a little, relay compounds are intermediates in your synthesis that you can easily obtain by degrading a cheap and easy to get natural product target, saving time/energy/money by skipping laborious steps. It was pretty common in the Woodwardian era, but since most NP targets now are targets due to their scarcity, it isn’t seen to often.

  25. maybeinyourworld says:

    You work at Vertex, nuf said

  26. Norepi says:

    So accurate! The comments shot around in my group are usually even more trivial, including things like:
    CHEMIST A: *hand-waving, slide-changing* For the Whatthehellomycin system, we really want the primary amine over here, because all other substituents we’ve tried kill all the activity, but we keep getting 12% yield on the last reduction, no matter what we do.
    CHEMIST B: The whatthehellomycin system looks just like noodlepantsamide!
    CHEMIST A: It is the same scaffold as noodlepantsamide!
    CHEMIST C: Why don’t you call it noodlepantsamide, then?
    CHEMIST A: Because it lacks the hydroxyl group at position 7!
    CHEMIST B: For the amine, why don’t you just make the azide?
    CHEMIST A: Because the azide isn’t commercially available.
    CHEMIST D: But the chloride is $0.80/g! Go through that!
    GROUP LEADER (who has been reading his date-book and ignoring the meeting) – Wait, which amine is this now?

  27. Cell biologist says:

    What a depressing and discouraging post. Reason enough to advise against doing synthetic chemistry in drug industry.

  28. Sili says:

    I think I used to be Chemist C at uni – knew too much textbook stuff, but no practical talent.
    Just to add insult to injury I’ve just started on a project management course (beats pottering around at home, at least).
    I guess I should be happy that it’s only been two months – but I’d really like something to do by now.

  29. Though it might sound depressing the scene just show a part of the reality. A vision of the whole picture can be obteined by reading the last chapter in the book ‘Drug truths’ by John L. Lamattina: “People often ask about how pharmaceutical scientists cope with the repeated failure in drug research.After all, more than 90% of the compounds that enter development never become approved medicines…”.

  30. Simon says:

    Do you ever have comp chemists in these meetings, and what kind of things do they say?

  31. daen says:

    Disclaimer: I Am Neither A Trained Chemist Nor Am I A Computational Chemist, I Am A Software Engineer Who Works With Chemists (IANATCNAIACCIAASEWWWC)
    But I have sat in on company science meetings at a small biotech which made large targetted combichem generated libraries. My job was to take the raw results from selection runs against a target, map them back into company compound identifiers and rank them. You would often end up with a huge number of promiscuous binders (to plastic, BSA whatever), then some oddballs where something had obviously gone wrong, then in among the noise would be a number of small (sometimes very small) signals. Watching the biologists and chemists play “why is this thing like these six other things but not like the twelve here” was fascinating. I just used to pray in those meetings that they wouldn’t ask me to rewrite or add to the analysis software again …

  32. Mu says:

    It’s missing the computational chemist who tells the synthetic chemist that the real reason for weak binding is that the ligand that’s put on in the last step (98% para yield, took a year to get that) needs to be meta, problem solved.

  33. clinicalpharmacologist says:

    Depressingly familiar, indeed. However, may be the real question is “what SHOULD such a meeting look like and how do we get there?”
    I am worried that the elephant in the room is, if we don’t get this sorted out, there isn’t going to be an industry to work in. Especially considering the uncomfortable and very believable details in the ROI thread.

  34. z says:

    I’m not sure I understand why so many people find this depressing, especially from the people who are scientists and should understand that science is not fast, flashy, well-understood, rationally designed, or any of the stuff that non-scientists often think it is. This looks like a routine monthly early/mid-stage chemistry meeting, and I don’t think that’s too bad.
    It takes time to synthesize compounds (often longer than you said it would at last month’s meeting because some stupid chemistry doesn’t work the way you expected it would), and it takes time to generate biological data on them. It takes time to come up with any useful models based on this data, and then more time to make analogs suggested by these models, only to show that the models were overly simplistic and not useful afterall. I think this only shows that medicinal chemistry is difficult and that we do not yet understand very much about how biological systems work. It’s not that our ♠approach is fundamentally flawed, it’ just that it takes time and slow incremental research to get anywhere.

  35. Clinical Development Monkey says:

    you could write another one, a year on. The same crummy compounds have been pushed through an animal model that doesn’t actually reflect the human disease, with equivocal results. Tox studies have been completed with 7 days exposure, at blood levels below those used in the animal efficacy model. Sadly, they can’t seem to dose the animals for longer than 7 days, and we’re dealing with a chronic disease. Nonetheless, the project team is still slogging on:
    Project leader: OK, upper management has allocated funding to fast track this to proof of concept. The Senior VP has said this is the most important compound in the portfolio. So everything we do now will be closely watched, and management will add comments to every document.
    We’ll plan on just doing a single-dose PK study in normal volunteers. We can’t afford to incorporate the PD markers that might show it’s hopeless. Once we get the PK we’ll want the fastest possible results from an early phase 2 study. We can only afford a single active dose arm, so we’ll go with the maximum tolerated. Sorry, no dose-response data. And we’ll cut costs by only doing source document verification on 20% of the endpoint data. We can get more cost savings by running it in eastern europe and some small third world countries. We’ll be sure to use adaptive design because that seems to make everything better.

  36. Anonymous BMS Researcher says:

    I have sat through MANY meetings very like this one, and in fact will be sitting through another one in a couple days (at about 4PM today I sent the Discovery Working Group leader my PowerPoint slides for said meeting). This rings very true, especially when it comes to the constant fiddling around to work resolve PK and Tox liabilities without losing potency.
    However, at the meetings I attend there are also lots of PowerPoint slides from the biologists reporting on how various molecules did in assays (in vitro at earlier stages, in vivo later). And on the biology side we have our own fun issues, especially when the rank ordering of compounds in each model organism is different and nobody is sure WHICH species is the most predictive of what will happen in humans.

  37. HappyDog says:

    You forgot the modeller. My meetings go something like this:
    MODELLER A: That compound is not predicted to be (insert desired ADME property here) for the following reasons . . .
    CHEMIST C: That’s not true, you guys can’t predict ANYTHING!
    MODELLER A: Actually, we have had good success with this compound in three programs in the past.
    BIOLOGIST B: Yeah, but you couldn’t predict the brain penetration of compound X.
    MODELLER A: Well, that was one compound. We predicted the other 30 correctly, and the one you are referring to was from a competitor that our model wasn’t even trained on because we have no data on their proprietary series of compounds.
    CHEMIST B: Well, if you miss one, then who knows what else you’re not predicting. It’s probably safer to ignore the models and test every compound in the series in the rat model.
    PHARMACOLOGIST A: Are you totally insane? Do you have any idea how expensive that is? I’m not going to sacrifice 100+ rats (or even 20 rats for cassette dosing)! I have a dozen other projects that require pharmacology support. Pick your best six.
    CHEMIST A: OK, we’ll go with those ones.
    MODELLER A: Look we’ve had good success with this model on this project, and those six are not predicted to have the desired properties.
    CHEMIST B: Shutup, you can’t predict anything. Medicinal chemists have the “recipe” for (desired ADME property).
    BIOLOGIST A: Um, none of those were soluble in the in vitro assay.
    CHEMIST A: Yeah, but in my experience that shouldn’t affect the in vivio results.
    Sad to say, but it’s a collage of things I’ve heard on project teams over the last year or so.

  38. Pratik .V. Amin says:

    if we are making drugs by me to mechanism and it takes so much time as well as lots of pounds investing to do so and still didn’t get result why we are not trying the alternative synthesis and computer program to modify drugs and to get result. if we can modify drug in computer and get effect we want in particular structure of compound we can do directly practicals on that compound rather then making lots of compound and do experiment on all of them. i am a student of greenwich university studying pharmaceutical science. And i am trying to make that software that can calculates effects of drugs in particular series from few compounds of that particular series.

  39. Pratik .V. Amin says:

    if we are making drugs by me to mechanism and it takes so much time as well as lots of pounds investing to do so and still didn’t get result why we are not trying the alternative synthesis and computer program to modify drugs and to get result. if we can modify drug in computer and get effect we want in particular structure of compound we can do directly practicals on that compound rather then making lots of compound and do experiment on all of them. i am a student of greenwich university studying pharmaceutical science. And i am trying to make that software that can calculates effects of drugs in particular series from few compounds of that particular series.

  40. Jose says:

    Best of luck with that endeavour, brave sir… Corey’s CAOS was a rousing success, too!

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