Editorial Cite This: Biochemistry 2018, 57, 469−469
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Introducing Biochemistry to Bedside
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pick one example). Another broad lesson that strikes anyone doing drug discovery is that we really do not know enough (yet!) about the biochemistry of health and disease. That leads to the smaller lessons from each individual project, the twists and turns that occur when what was supposed to be a straight line, back in the earlier slide decks, caroms off various hidden obstacles out in the real world. This journal is now starting a series of articles about various recent drug approvals, with an eye to their biochemical details and how these have translated into the clinic. These are the winners, then, the relatively rare cases in which mechanism, in vivo behavior, and chemical matter overlapped enough to leave a compound behind. Looking over these will provide a perspective across the idiosyncracies of a number of different disease areas and compound types, but there will still be plenty of things in common, too, b cause every successful drug has to run some of the same obstacle courses in the laboratories and in living systems. The strongest similarities, though, are the insights needed to start off each project, and the perseverance to see each of them through to their conclusion; those, you’d have to think, will never change.
very new drug starts with an idea. Some of these ideas are obvious, or at least seem that way to later observers, while others are well-hidden by anyone’s standards. But if you trace a successful discovery project to its very beginning, it will lead you back to a spot between someone’s ears. A thought got started with the phrase “I’ll bet that if you ...” or “I wonder if you could ...”, and things went on from there. And the idea doesn’t even have to be as definite as that. Isaac Asimov once said that the real sound of a scientific breakthrough was not a shout of “Eureka”, but someone saying “Hmm, that’s funny”. Many are the projects that got their start with just that phrase. Developing such an idea into an approved drug, though, is a notorious long shot. The success rate across clinical trials is reckoned to be only approximately 10−15%, but the failure rate of earlier-stage ideas and projects is surely both larger and largely unrecorded (and, in some cases, unrecordable). It is easy to sit back from a comfortable position and decide that these unsuccessful ideas must all have been inferior in some way (and even inferior in some way that might have been recognized earlier), but that is not always the case. Not by any means; a great many extremely compelling and plausible ideas have wiped out along the way when things once again turned out to be more complicated than anyone expected. Every experienced researcher in this business has had a few sure things blow up on them, and after a while, it becomes apparent that there are not actually any sure things. A look back through a few 20-year-old journals will reveal many targets that multiple research groups thought were worth a lot of time and effort but in the end never yielded any actual drugs. Some of the projects we are working on now will fill that space 20 years from now, and there is no way around that (yet!) and no way to say just which ones they will be. This makes it all the more worthwhile to look into the ideas that did make it all the way and the drugs that were approved. Broad themes emerge from these retrospectives. Even if no given project is likely to succeed, on average, there are still modes of action that are clearly more likely to succeed than others. If we eliminated all the enzyme inhibitors and GPCR ligands, for example, we’d have a much leaner and far less impressive pharmacopeia. At the other end of the scale, working through (say) the number of successful small-molecule modulators of transcription factors will not take up much of your time (yet!). Another theme that shows up unmistakably is that medicinal chemists are better at gumming up the biochemical works than they are at making them work more smoothly. For evolutionary reasons, this would almost have to be true. The large number of inhibitors and antagonists compared to the activators and agonists bears that out; drug discovery chemists are much more accustomed to throwing well-placed wrenches into carefully selected gears, the better to bring just the right part of the cellular machinery to a shuddering halt. But even the classically productive areas for drug discovery can be full of enough trouble for anyone (working on enzyme inhibitors sounds fine until you try it on a phosphatase, just to © 2018 American Chemical Society
Derek B. Lowe*
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Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139-4133, United States
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Corresponding Author
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[email protected]. Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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ACKNOWLEDGMENTS TOC graphic adapted with permission from xkcd.com comics 644, 683, 1471, and 1674.
Received: December 5, 2017 Published: February 6, 2018 469
DOI: 10.1021/acs.biochem.7b01217 Biochemistry 2018, 57, 469−469
