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The Hard Targets: How Far Along Are We?

I wrote here about whole classes of potential drug targets that we really don’t know how to deal with. It’s been several years since then, and I don’t think that the situation has improved all that much. (In 2011 I reviewed a book that advocated attacking these as a way forward for drug discovery).
Protein-protein interactions are still the biggest of these “undruggable targets”, and there has been some progress made there. But I think we still don’t have much in the way of general knowledge in this area. Every PPI target is its own beast, and you get your leads where you can, if you can. Transcription factors are the bridge between these and the protein-nucleic acid targets, which have been even harder to get a handle on (accounting for their appearance on lists like this one).
There are several chicken-and-egg questions in these areas. Getting chemical matter seems to be hard (that’s something we can all agree on). Is that because we don’t have compound collections that are biased the right way? If so, what the heck would the right way look like? Is is because we have trouble coming up with good screening techniques for some of these targets? (And if so, what are we lacking?) How much of the slower progress in these areas has been because of their intrinsic difficulty, and how much has been because people tend to avoid them (because of their, well, intrinsic difficulty?) If we all had our backs to the wall, could we do better, or would we generate just a lot more of the same?
I ask these questions because for years now, a lot of people in the industry have been saying that we need to get more of a handle on these things, because the good ol’ small-molecule binding sites are getting scarcer. Am I right to think that we’re still at the stage of telling each other this, or are there advances that I haven’t kept up with?

14 comments on “The Hard Targets: How Far Along Are We?”

  1. B says:

    I think that in many cases we aren’t always properly addressing the question. As we all know, much of drug discovery currently focuses on high-throughput screening, using some form of enzymatic read-out and choosing your best actives.
    This may not always be the proper way to go about it. I have seen numerous cases where finding an active that inhibits enzymatic activity by ~20% is actually an allosteric modulator that can almost completely inhibit other protein-protein interactions despite only appearing to have a minimal effect on the assay. We need to be careful in how we interpret results, especially those coming from HTS efforts.
    I think there is also too much weight given to “Lipinski” space. In some ways it is certainly tried and true, but we all know of many cases where compounds completely ignore these ‘rules’. Efforts need to be made to characterize other potential leads, which I think is a significant gap in our current understanding of drug-like molecules.
    So I don’t think we are there yet. But I think we are close. I think that focusing on traditional ‘drug-like’ small molecules will not lead us towards inhibiting PPIs. We need to find new criteria, new drugs (such as targeted macrocycles with large steric bulk or allosteric modulators) and new ways to interpret our assays so that we don’t miss those compounds that could be inhibiting PPIs but are flying under the radar.

  2. Chrispy says:

    Protein-protein interactions are completely druggable as long as they are outside of cells. Antibodies are a great example (Humira, Stelara, Actemra) as are fusion proteins (Enbrel, VEGF Trap-Eye). Cyclosporin is a phosphatase inhibitor that operates (intracellularly) by causing protein-protein interactions; I guess that’s why it is the poster child for what we could do if we ignored Lipinski. Part of the problem is chemical tractability, since as these molecules get large they get expensive and difficult to synthesize. Unless you are a fungus, or a CHO cell…

  3. 59er says:

    I have been working on an orphan nuclear receptor problem for two years now and thinking about it sufficiently hard has lead me to the conclusion that you HAVE to push your understanding and imagination about the complex systems to move even a little way forward. This hints at a way forward
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852352/
    Even when a target looks intractable, remember all of our definitions of binding sites are nearly always based on static biomolecules. Transcription complexes are anything but static, even on the much simpler isolated TF components.
    Some targets are complex and ‘hard’ but achievable targets. Strive on!

  4. simpl says:

    Easy case, but aren’t the peptide analogues working on other proteins, like pasireotide? You find your peptide hormone, work out which part is interacting with something, start looking for analogues of the interesting bit, and Bob’s your uncle.

  5. pharmacologyrules says:

    Too many conduct drug discovery based on papers they read–papers often authored by scientists that work at companies with a less than stellar drug discovery history. We should realize many of these papers provide guidlines but not hard and fast rules. Too often the project team is happy they got rid of hERG or high protein binding–neglecting the fact they also lost target engagement.

  6. Johannes says:

    Calling them “undruggable” is negative thinking -c’mon, aren’t you a team player?

  7. barry says:

    if there’s a class of “hard targets” more important than Protein-protein-interactions, it’s mammalian transcription factors. Everyone knows the correlation of e.g. myc mutation with cancer. No one’s doing anything about it because we don’t know how.
    Tularik spent years and millions screening for small-molecule modulators of mammalian transcription factors and found zero. The closest things we have are steroids (which modulate transcription indirectly).

  8. gippgig says:

    Relevant article: No new meds With drug firms in retreat, the pipeline for new psychiatric medications dries up, cover story, Science News magazine, Feb. 23.

  9. biochembelle says:

    One of the ASPET sessions at Experimental Biology last year was focused on protein-protein interactions. Based on my perspective of the field and some of the talks at EB, the assays are there (though some targets may still present problems), but the compounds aren’t.
    David Fry of Hoffmann-LaRoche suggested that typical chemical libraries simply don’t have good scaffolds for targeting protein-protein interactions. Their success with nutlins for p53/MDM2 was literally a 1 in a million hit. He talked their development of chemical libraries with PPI-targeting scaffolds. A major feature was increasing dimensionality, or giving molecules more 3D shapes instead of the relatively flat molecules that inhabit most libraries.
    Fry did voice a concern that few groups are working on PPIs because they are tough targets. He and Michelle Arkin (UCSF) both commented on major issues being low binding affinities compared to other interactions and large binding interfaces, which mean larger molecules that don’t obey Lipinski rules.

  10. petros says:

    In January PPINet (http://ppi-net.org/) organised a 2 day meeting on Protein Protein Interactions at the Royal Society. This highlighted many of the current problems and the generally non-Lipinski type hits that are identified.

  11. Teddy Z says:

    Binding assays….binding assays…binding assays. To find hit matter for PPIs, use a binding assay, like NMR. To get around the issue use fragment libraries to enable greater diversity. I realize I sound like a broken record here.
    For full disclosure, I have a vested economic and scientific interest in Fragonomics ™. 🙂

  12. sgcox says:

    One of the most arguably successful PPI inhibitor in clinic is Rapamycin and its derivatives. However, Rapamycin is not a PPI inhibitor per se, It is in fact a _promoter_ of Protein-Protein Interaction between mTOR and FKBP12. Good luck finding that with “binding assays” or “displacement assays” without a prior knowledge of the natural product MOA.

  13. Ted says:

    Darwin Molecular had a great genomically derived target, dredged up from the 90’s surrogate drug effort on a SA sclerosteosis population. My recollection is that two copies of the defective gene and your bones grew so dense that your brain would be crushed by the time you reached maturity. One copy, you avoided that and had bones as hard as steel.
    The local chemistry effort was greatly disappointed to find that the protein of interest was soluble…
    It’s been about 13 years now, the Darwin (later Chiroscience, later Celltech) folks have been dispersed to the winds.
    Amgen “owns” the target now, and the antibody AMG-785 is slowly winding its way through the clinic. I’ll always feel a bit wistful about not getting to work on it, but we really just didn’t have the tools.
    -t

  14. anonymous says:

    @1 :
    “I have seen numerous cases where finding an active that inhibits enzymatic activity by ~20% is actually an allosteric modulator that can almost completely inhibit other protein-protein interactions despite only appearing to have a minimal effect on the assay.”
    Please….do tell (about the numerous cases, that is) !

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