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Why Don’t We Have More Protein-Protein Drug Molecules?

Almost all of the drugs on the market target one or more small-molecule binding sites on proteins. But there’s a lot more to the world than small-molecule binding sites. Proteins spend a vast amount of time interacting with other proteins, in vital ways that we’d like to be able to affect. But those binding events tend to be across broader surfaces, rather than in well-defined binding pockets, and we medicinal chemists haven’t had great success in targeting them.
There are some successful examples, with a trend towards more of them in the recent literature. Inhibitors of interactions of the oncolocy target Bcl are probably the best known, with Abbott’s ABT-737 being the poster child of the whole group.
But even though things seem to be picking up in this area, there’s still a very long way to go, considering the number of possible useful interactions we could be targeting. And for every successful molecule that gets published, there are surely an iceberg of failed attempts that never make the literature. What’s holding us back?
A new article in Drug Discovery Today suggests, as others have, that our compound libraries aren’t optimized for finding hits in such assays. Given that the molecular weights of the compounds that are known to work tend toward the high side, that may well be true – but, of course, since the amount of chemical diversity up in those weight ranges is ridiculously huge, we’re not going to be able to fix the situation through brute-force expansion of our screening libraries. (We’ll table, for now, the topic of the later success rate of such whopper molecules).
Some recent work has suggested that there might be overall molecular shapes that are found more often in protein-protein inhibitors, but I’m not sure if everyone buys into this theory or not. This latest paper does a similar analysis, using 66 structurally diverse protein-protein inhibitors (PPIs) from the literature compared to a larger set (557 compounds) of traditional drug molecules. The PPIs tend to be larger and greasier, as feared>. They tried some decision-tree analysis to see what discriminated the two data sets, and found a shape description and another one that correlated more with aromatic ring/multiple-bond count. Overall, the decision tree stuff didn’t shake things down as well as it does with data sets for more traditional target classes, which doesn’t come as a surprise, either.
So the big questions are still out there: can we go after protein-protein targets with reasonably-sized molecules, or are they going to have to be big and ugly? And in either case, are there structures that have a better chance of giving us a lead series? If that’s true, is part of the problem that we don’t tend to have such things around already? If I knew the answers to these questions, I’d be out there making the drugs, to be honest. . .

14 comments on “Why Don’t We Have More Protein-Protein Drug Molecules?”

  1. Anne says:

    My rotation PI is very interested in this question and there’s a couple projects in the lab that are dedicated to a new approach to the problem. His fundamental idea is to link two functionalities together: one recruits an ubiquitous protein (FK506-binding protein) and the other binds a protein whose interaction we want to inhibit. The recruited protein then becomes a bulky blocker that prevents other proteins from getting into position to create the protein-protein interactions. He’s applied the concept to inhibiting amyloid-beta aggregation and inhibiting HIV protease, and is now expanding into antibiotics. This isn’t my project in the lab, but I find it really interesting.
    Here’s the page that describes his research: Gestwicki Lab
    And here’s a review article he did on the subject: Beyond inhibitors

  2. retread says:

    An interesting paper along this line is [ Nature vol. 462 pp. 171 – 173 (commentary) and 182 – 188 (the paper) ’09 ]. It used a stapled peptide (interesting in itself made by using metathesis on artificial alpha amino acids with an olefinic side chain) which formed a very stable alpha helix to break up the interaction of MAML1 with the intracellular domain of Notch and CSL. One wouldn’t think something this big could get into a cell, but by adding lots of arginines to the stapled peptide it did.
    So the paper is triply interesting, breaking up protein/protein interaction, stapled peptides and getting the whole thing into cells. All three approaches should be quite generic.

  3. Anonymous says:

    Anne,
    It is an interesting idea. A variant I’ve heard of the same idea involved not only using the ubiquitous protein as a blocker, but recruit one that has an actual function. You could, for example, recruit a ubiquitin ligase that would tag the protein you wanted to inhibit for destruction, theoretically improving your molecule significantly. I’ve never heard of anyone actually getting it to work with a small molecule, though.

  4. Dr Nick says:

    uggh, epic fail on the link.
    try this: http://tinyurl.com/y983lz6
    I’m not very good at this Interwob thing.

  5. Anonymous says:

    Hi Dr. Nick!
    That is interesting! Thanks for the link!

  6. JC says:

    I would go ask the guys in the building next door who were trying this protein-protein stuff but they went under ages ago.

  7. milkshake says:

    its rather hard to make the molecules that have some chance at this – the large macrocyclic beasts with multiple stereocenters. (I wonder if anyone tried to target protein-protein interactions with cyclic peptoids synthesized in a combichem fashion).

  8. Fred says:

    good stuff JC.

  9. Jose says:

    Maybe from pipeline earlier, or elsewhere, but rather like using a kayak to stop a battleship engagement, n’est pas?

  10. barry says:

    re: Jose #10
    more optimistically, one can note that it only takes a small pebble to keep a whole ski-boot from fitting. Binding of GDP to Ras precludes binding of Ras to Raf. However, the dearth of effective small-molecule inhibitors of PPIs suggest that it’s not easy to stick the right pebble in there.

  11. DrJimbo says:

    A colleague sent this to me, so I can’t take credit for it, but:
    http://wavefunction.fieldofscience.com/2008/05/myths-about-disrupting-protein-protein.html

  12. Petros says:

    Some of the work from Andy Hamilton’s group is intersting in this regard, and he certainly describes a logical approach to the problem

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