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Target Invalidation

Target validation is a key process in drug discovery, naturally. But it’s worth remembering that target invalidation happens more often, and is also important. The first project I worked on in the drug industry proved pretty conclusively that selective antagonism at the D1 dopamine receptor is not an effective therapy for schizophrenia, despite some predictions that it would just be the bee’s antipsychotic knees. I have just plain lost count of the number of targets I’ve seen invalidated since then – some in the clinic, and some well before that point. Most of our ideas in this business turn out to be mistaken.

I mention this because of a recent case in the epigenetics field. There are a lot of potential targets there, but we really don’t know all that much about how valid many of them are (or, as that news item the other day showed, what else they might be doing). One that’s been advanced for some types of lung cancer and other conditions is SMARCA4, and a good deal of work has been going on with that target for several years now.

Maybe not so much now, though. A group at Pfizer recently published a pretty definitive study showing (among other evidence) that an effective SMARCA4 ligand (PFI-3) is still unable to have the desired effects in tumor cells. Knockdown of the protein made it look like a good idea, but it appears that the ligand doesn’t go all the way to effects on chromatin. Instead, it’s the ATPase domain, rather than the ligand-binding one, that looks like a real therapeutic target.

Pfizer had presented this work at meetings before this publication came out, and I’m told that a number of programs (in academia and industry both) came to a juddering, dust-spewing halt once people saw the data. But that’s science for you – everything is provisional.

11 comments on “Target Invalidation”

  1. Small Biotech says:

    This is just the reason for phenotypic screening! Of course, it is possible that the cellular phenotype used in the screen itself is devalidated, but screening at the level of cellular phenotype removes one layer of reductionism… screening at the organismal level removes another (though perhaps adding another confounder of non-human species)….

  2. annon says:

    Would PTP1-B be falling into that category?

  3. Ted says:

    @annon

    Yes, at least in my book.

    Throw CXCR2 onto the pile as well…

    -t

  4. bhip says:

    Looking for drugs which synergize with Checkpoint inhibitors for cancer (i.e. PD-1, etc) may resurrect a number dead compound classes i.e. chemokine receptor antagonists

  5. JPB says:

    A nice paper. Should say, though, “a collaboration between MD Anderson and Pfizer … ” for its origin.

  6. Lionel C. says:

    Is there any specific database that list invalidated(/validated) target for one or an other disease ?

  7. KissTheChemist says:

    What a coincidence…MY first ever project was selective antagonists at Dopamine sub-types, too! I felt like we were really onto something……..doh! As a med chemist I’ve long since accepted the most important players in pharma are the….gulp… the BIOLOGISTS who validate the target. Lately its been the guys who set up the cellular screening for our lovely potent enzyme inhibitors who get to can my projects.

  8. cdsouthan says:

    An interesting twist on the BACE2 diabetese target – or not story was just presented at ACS http://cdsouthan.blogspot.se/2014/12/bace2-as-diabetes-target-or-maybe-not.html

  9. TX raven says:

    @ KissTheChemist

    I challenge your assertion that “the most important players in pharma are the….gulp… the BIOLOGISTS who validate the target.” Indeed, I think that is part of the problem: thinking that in drug discovery one line runs the show and the others are “support”. That disengages others…

    Yes, biologists (plural) are generally key contributors to the TV strategy, and are responsible for providing the data resulting from such studies (in vitro or in vivo, in-house or at CRO). But what about other key pieces of support, like target engagement, exposure at the right tissue, potential off-target tox effects, PKPD, formulation, discovery of chemical tools, and so on?

    IMHO, the exercise called target validation happens in a big tent environment, highly interactive, where folks from different areas bring their input (bioanalysis, statisticians, medicinal chemists, chemical biologists, geneticists, molecular pharmacologists, HTS folks, in vivo pharmacologists, etc) and a good science discussion leads to an appropriate risk assessment.

  10. Mfernflower says:

    Go ahead and add Gamma secretase to the pile.

    1. cdsouthan says:

      MF, Its important not to conflate different validation evidence strands. Few targets are more solidly genetically validated than Gamma secretase, even if the crossover with Notch processing confounds clinical progression. The BACE1 situation is the opposite, no direct genetic validation at all (only indirect via APP mutations) but the rodent, primate and Phase I studies look at least hopeful

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