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.