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October 13, 2010
A Cautionary Tale
For those who haven't seen it, I heard Adam Renslo of UCSF present this work yesterday. His group was looking for inhibitors of cruzain, a target for Chagas' disease, which is certainly a worthy cause (and a tough target). They found a series of oxadiazoles, which are, to be sure, rather ugly (but no uglier than a lot of chemical matter you see in the kinase field, among others). They had affinity, they had reasonable SAR, and the team drove the potencies down against the target. . .only to find, late in the game, that it was all an illusion.
These compounds are aggregators. (That link takes you to a post about a follow-up paper from the UCSF folks, covering this debacle and others). What's striking is that this artifact (compound aggregation under the assay conditions) mimicked a plausible SAR - it wasn't just some random thing that made the numbers hard to interpret. No, it looks like Renslo and his team ended up optimizing for aggregation. As he put it in his presentation, "You'll find what you're looking for".
His other quote at the end of the talk was "Small molecules are much stranger than we've been led to believe", and I can't argue with that one either. Before anyone makes a comment about how his group should have checked their assay more thoroughly, or how they shouldn't have been trying to push such an unpleasant-looking series of compounds anyway - in general, about how this wouldn't have happened to you - pause for a moment, and be honest. Renslo was in this paper, and I thank him for it.
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