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February 21, 2013
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?
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