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A Closed Loop

This is not a paper that’s going to make everyone who reads it happy, but it needs to be read anyway. A collaboration between the University of Helsinki, LifeArc (which looks to be one of the small companies in the former Stevenage pharma campus) and Cyclofluidic reports development of inhibitors against hepsin, a serine protease enzyme that is a potential cancer target.

So far, so uncontroversial. The same group had identified a micromolar hepsin inhibitor from some late-1990s urokinase inhibitor chemical matter, but this compound (naturally) still had activity against urokinase. The goal was to improve potency while working away from urokinase, which is just the sort of thing that med-chem teams everywhere spend their efforts on. The enzyme seems to need an amidine/guanadine functional group for potency, and a screen of commercially available derivatives gave another micromolar hit with less urokinase activity as a new starting point. 142 new compounds were prepared, optimizing along until a final compound was reached with 22 nM potency and 200x more selectivity in the counterscreen.

Which is good: that’s what a team of medicinal chemists are there to do. What makes this paper interesting (and those who have heard of Cyclofluidic will have already caught on) is that the chemistry was automated in a flow reactor, and the enzyme assay results were fed back into the software which generated SAR predictions for the next round of synthesis. Importantly, the screening assay is part of the automated system as well, and the entire loop (synthesis/purification/assay) is claimed to take around 90 minutes.

The way this actually worked was that the automated system would run through a particular SAR space, generating a series of compounds, and at that point the humans involved would have a look at how things were going. Subsequent runs might include new SAR building blocks or changes to the algorithms that evaluated the results. So it’s not like they walked away for a weekend and came back 142 compounds later to a selective nanomolar inhibitor – but neither is it the case that people made all these compounds and selected the next ones to make, either. This was machine-assisted compound development, very much analogous to what Gary Kasparov has termed “centaur” chess, where humans evaluate their ideas with the aid of software to come up with even stronger moves.

It needs to be noted that the chemistry involved was very straightforward (amide and sulfonamide formation, for the most part) and the assays were quite robust. This was close (as have been the other things reported in this vein) to a best-case example for such closed-loop automated SAR work, but then again these are early days. I also noticed that several of the co-authors on the paper now have different addresses, which makes one wonder how long ago this project was actually done. My point is that automated synthesis (thanks to human ingenuity) is getting better all the time, as are the methods for in-line assays and especially those for evaluation of chemical space and SAR. Thanks to human ingenuity, we are very likely going to be freeing up time to apply that ingenuity to other things than banging out obvious SAR compounds.

If, though, you are a human chemist (as so many of my readers are, to steal a joke from G. K. Chesterton), and you feel that you are watching your livelihood being stolen right in front of your eyes, consider what in this case the machines are taking from you. You are being deprived of the chance to do some of the most boring chemistry in the world in the most routine fashion imaginable. My own feelings are that any machine that takes away from me the necessity to crank out 142 amide reactions by hand is welcome to it. This is the med-chem equivalent of doing the laundry, and I have a machine for that, too.

24 comments on “A Closed Loop”

  1. Isidore says:

    One cannot argue with the logic of machines doing the tedious, repetitive, boring stuff, thus allowing humans to focus on generating exciting, innovative, unique ideas and implement them. But it all comes down to numbers: For each scientist who has the smarts, the experience and the drive to do the latter there is at least one and possibly more who don’t and who, until the machines took over, were doing the tedious, boring, respective stuff and many didn’t much mind it. What are we going to do with them? I am not suggesting that the answer is to continue employing people in jobs that are, by rights, becoming obsolete so that unemployment doesn’t go up, but I also don’t have another good answer.

    1. Derek Lowe says:

      That’s the real question, and not just for med-chem. . .past cycles of automation have not led to unemployment in the long run, but that’s not a law of nature.

      1. Hap says:

        Did it lead to worse employment? If I lose my job, I can get something else, but I probably won’t be in my field and won’t either use my knowledge or make as much money. I assume that that’s at least part of the Trump attraction – a lot of people went from having jobs they were happy with to being service workers with limited pay and prospects, and they are/were hoping that Trump and Republicans would bring their jobs back. Is this real or inaccurate perception?

        1. ScientistSailor says:

          The Trump attraction is pure idiotic racism. Please don’t try to excuse it with anything that might be legitimate, as you just give them cover.

          Silence is the voice of complicity.

          1. I voted for neither says:

            So 8.1 million people (the number of Obama–>Trump voters) became bigots over the course of just 4 years? Seems highly unlikely. Far more likely that partisan antipathy has clouded your judgement.

          2. Hate the Elite says:

            I didn’t vote for trump, but if you are looking for why he won and how your candidate can win in the future maybe you should do some self reflection and think deeper about others before writing off half the country. ‘I voted for neither’ hit the nail on the head, 8 million people didn’t just suddenly turn racist. Blue collar union voters made the flip, think harder about why, this isn’t buzzfeed.

          3. ScientistSailor says:

            Those people (however many there really are) support and enable racism and hate, which is no different than being racist and hateful.

          4. Anon2 says:

            There are only 14.8M union members (blue collar or not) in the US in 2017. Do you really think that over half of them voted for Obama and then Trump? The numbers suggest that many non-union members were involved.

          5. ScientistSailor says:

            @ I voted for neither: I don’t know why you assume ‘partisan antipathy’ from my statement about bigotry. It’s really simple: one party offered corruption, sleaze and condescension, the other offered corruption sleaze and bigotry.

          6. fajensen says:

            … or Economics! What are all the losers in the Competition- and Globalisation- Games imposed upon society gonna do? Those great neo-liberal thinkers currently running the show are offering only two answers: Their solution to any human problem is “Go Die” and ” Because Markets” for anyone asking “Why?”!

            This is bound to twigger some folks; surely not all of those are “racist” and maybe if there were Options for political dissent other than The Donald, Le Pen, SD and AFD then one would assume people would prefer those avenues to express their outrage?

            In my opinion, it’s no good to have a political system that is so controlled as it is now. When “everyone” agrees on a very narrow middle-ground (“stability Zum Endzieg”), then that leaves the nut-bar- and not so nut-bar-but-evil- fringes free to suck up all the dissenters and losers.

            I agree with the attached article in that society needs to stop producing so many losers – or else the losers will take over society through sheer weight of numbers!

            The populism backlash: An economically driven backlash

            Luigi Guiso, Helios Herrera, Massimo Morelli, Tommaso Sonno 17 May 2018

            There has been some disagreement over the roots of the recent rise of populism in Europe. This column examines variations in exposure to economic shocks and in ability to react to them in different regions of Europe to show that the cultural backlash against globalisation has been driven by economic woes. In regions where globalisation was present but that have benefited economically, there has been no such backlash and the populist message has retreated. The message is clear: if one wants to defeat populism, one must defeat first economic insecurity.


          7. Lola says:

            @fajensen: And to ameliorate economic insecurity in the west would require the return of jobs effectively exported from the first world (in this case America) to the 3rd world (China, for instance). The steel industry is an index example. What brought millions out of poverty in places like China came at the expense of lower middle class jobs in the west. The likelihood of these jobs ever returning in the west is zero to none. Globalisation was not, despite the Michael Porters and Allen Greenspans of this world a ‘win-win’ situation. It was instead a ‘win-lose’ one, and Trump is the most recent (and misguided) attempt at addressing it. The question remaining: will Trump’s voters ever come to realise their demigod cannot help them, and in fact benefitted himself personally from globalisation?. He’s hardly likely to do anything that compromises his own wealth, or that of his benefactors, but at the same time I’m not confident that globalisation’s victims will ever put 2+2 together – rather they’ll be swept up in whatever simplistic excuse or obfuscation The Trump can come up with next – blaming ‘foreigners’ is happening now and has almost run it’s course, but I’m not sure what else he’s going to be able to project their angst onto next.

      2. biotechtoreador says:

        “past cycles of automation have not led to unemployment in the long run”.

        It’s the ‘long run’ that’s the kicker here. While there’s clearly no use in Luddite-like railing against inevitable technological advancement it’s worth bearing in mind JM Keynes admonition.

  2. A chemist says:

    Not to diminish the work, but the SI for this paper is interesting. Very minimal compound characterization data is provided. I wonder if this will be the future if we go towards more automation and micro scale reactions. I’ve always been of the opinion that if you don’t have the NMR, you didn’t make the compound. You won’t always be able to get full compound characterization and don’t always need to, but if you are publishing structures then it kind of does the chemical literature a disservice not to have it.

    1. tlp says:

      At least one med-chem lab I know used to characterize all compounds solely by LCMS. If it hits the target then you go back and take NMR and HRMS. I can imagine how in principle it may generate bunch of false negatives but if you are doing only (sulfon)amide coupling the risk-benefit ratio is OK. I guess, there’s not much progress in staring at 1D NMR (plus 13C?) of a hundred of very similar inactive molecules, while in the same time you could setup another couple of dozens of amide couplings.

  3. Hap says:

    I don’t think that we have found good uses for the people who are displaced by technological change – mostly they get discarded, and never find something else that uses their capacities, although at least some can find something that uses their capacities.

    We also seem to be in a “cheaper rather than better” mode of production, so that increases the likelihood that people will be discarded and that they will be unlikely to find useful work. Not liking the circumstances doesn’t make them not so, but it means that people are unlikely to welcome them with open arms.

    1. anoano says:

      When micro-wave with multi vials were introduced in the lab to speed up things, people did not complain much. At the end it took some of the time off our hands to do something else. Can see what’s described in the paper as fancy combi-chem and another tool for SAR instead of something taking our jobs.
      Still other properties to look at than just potency and lipophilicity.

  4. Chris Swain says:

    LifeArc, was formerly known as MRC Technology, evolved Medical Research Council (MRC)

  5. Uncle Al says:

    Carpentry could yield to CNC machining and solid printing – and perhaps often should. However, removing wetware also removes “What the Hell?” and “Look at that!” Incremental progress is not epiphany if the “obvious” answer lies off-track.

    Epiphany rings the net retained earnings bell. You still need good people – and more so if your competition has the same automation.

    1. Anonymous says:

      Readers only need to go back to the preceding Pipeline on “Fluoroquinolone Trouble Untangled” to find out about the accidental discovery of the quinolone antibiotics: human pursuit of a curious impurity from another project. One of the comments on the quinolone linked post mentions that the Beecham group that discovered compactin as a failed antibiotic did not look beyond that. The Japanese company that isolated the same compound from another fungal strain at around the same time looked beyond that to identify it as the first in class HMGCoA reductase inhibitor (statin).

      I don’t want to imply that the Beecham scientists were just robots. It could have been management USING them as robots to just find or make more compounds, not to find and make more drugs.

      (This is supposed to be a reply to Uncle Al’s post. We’ll see if I hit the correct Reply button.)

  6. Anon says:

    The era of developing small molecule drugs is pretty much over anyway, so automating the process doesn’t seem like much of a threat!

    1. Lola says:

      @anon: do you really think so ie. few small molecule opportunities left? That is indeed depressing!

  7. Shazbot says:

    What isn’t tedious, boring, repetive stuff to someone? I can’t think of anything.

  8. Notbot says:

    The ‘Former’ Stevenage pharma campus Derek? Not yet!

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