Here’s a new piece by Stuart Schreiber that lays out a shift in thinking that many people in the chemical biology field have been experiencing over the last few years. Medicinal chemists are used to making functional drug candidates – and by “functional” I mean compounds that make protein targets do something. For an enzyme, that usually means an inhibitor, because it’s always easiest to gum up the works, and the same goes for antagonists of receptors. But you can, of course, have full agonists, partial agonists, inverse agonists and all everything in between, and for enzymes you can have allosteric inhibitors and (rarely) activators as well. But what all of these have in common is functionality.
A great many assays are set up to detect such functional changes, naturally, looking for changes in some output in the protein or downstream in a cell. But you can also have compounds that bind to some protein without really doing much to its activity. Those will be silent in such functional assays, but you can pick them up with biophysical techniques like NMR, SPR, etc. DNA-encoded library screens also pull out binders, rather than screening on function. But in the past, having a binder that didn’t do anything didn’t necessarily get you very far – a difference that makes no difference, etc. What people would do with the results of such assays, likely as not, was to funnel them right into a lower-throughput functional readout and toss the compounds that did nothing. Which was sometimes all of them.
That’s changing, though. The most obvious technique working this way is targeted protein degradation. If you have something that binds to your target of interest, even if it doesn’t affect it by itself at all, you could imagine using that as a handle to engage the ubiquitination/proteasome machinery to drag the protein itself off to the compost heap. But it’s become increasingly clear that small molecules can (at times) cause two proteins to stick together. Consider the poster child for this mechanism, rapamycin: it binds tightly to FK506-binding proteins, and the resulting surface turns around and binds to mTOR proteins/complexes. But that’s a dramatic example, and it doesn’t stop there. Just binding a compound to a protein somewhere may not seem to affect that protein’s direct functional readouts, but (on closer inspection) it could alter its conformation or the surfaces it presents in ways that affect binding to its various partners.
These may well not be obvious – perhaps they’re not happening anywhere that your functional assay is looking, or only happen under certain conditions. Such binding events could also affect stability or localization of proteins as well, or their (many) posttranslational modifications. It’s not surprising that it’s taken years to become aware of such things and to start to take advantage of them, because we really haven’t had the tools to look at such broad ranges of behavior for very long. The number of possible interactions that a given protein can make is pretty intimidating – for some of them, it’s downright terrifying – and these can (and do) vary by cell type, environmental conditions, phase of the cell cycle, and so very much on.
Schreiber’s article goes into these and more, and suggests ways that the drug discovery/chemical biology/cell biology community might go about looking for these things systematically. This is a large landscape, and we know zilch, to a good approximation, about a lot of it. But it’s absolutely worth exploring, because we may be able to find ways to attack targets and pathways that until now were considered ridiculously out of reach for small molecules. So all you small-molecule folks: here’s the frontier, and here’s how you can find yourself back in the highlands, surveying unknown territory. Come and get it!