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July 25, 2013
Kurt Deshayes At The Challenges in Chemical Biology Conference
Kurt Deshayes of Genentech has been speaking at the Challenges in Chemical Biology meeting, on protein-protein inhibitor work. And he's raised a number of issues that I think that we in drug discovery are going to have to deal with. For one thing, given the size of PPI clinical molecules like ABT-199, what does that tell us about what makes an orally available molecule? (And what does that tell us about what we think we know about the subject?) You'd think that many (most?) protein-protein inhibitors will be on the large side, and if you were to be doctrinaire about biophysical properties, you wouldn't go there at all. But it can be done - the question is, how often? And how do you increase your chances of success? I don't think that anyone doubts that more molecules with molecular weights of 1000 will have PK trouble than those with molecular weights of 300. So how do you lengthen the odds?
Another point he emphasized is that Genentech's work on XIAP led them to activities that they never would have guessed up front. The system, he points out, is just too complicated to make useful predictions. You have to go in an perturb it and see what happens (and small molecules are a great way to do that). I'd say that this same principle applies to most everything in biochemistry: get in and mess with the system, and let it tell you what's going on.
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