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June 25, 2012
A Kinase Inhibitor Learns Something New
Here's another reminder that we don't know what a lot of existing drugs are doing on the side. This paper reports that the kinase inhibitor Nexavar (sorafenib) is actually a pretty good ligand at 5-HT (serotinergic) receptors, which is not something that you'd have guessed at all.
The authors worked up a binding model for the 5-HT2a receptor and ran through lists of known drugs. Sorafenib was flagged, and was (experimentally) a 2 micromolar antagonist. As it turns out, though, it's an even strong ligand for 5-HT2b (57 nM!) and 5-HT2c (417 nM), with weaker activity on a few other subtypes. This makes a person wonder about the other amine GPCR receptors, since there's often some cross-reactivity with small molecule ligands. (Those, though, often have good basic tertiary amines in them, carrying a positive charge under in vivo conditions. Sorafenib lacks any such thing, so it'll be interesting to see the results of further testing). It's also worth wondering if these serotinergic activities help or hurt the drug in oncology indications. In case you're wondering, the compound does get into the brain, although it's significantly effluxed by the BCRP transporter.
What I also find interesting is that this doesn't seem to have been picked up by some of the recent reports on attempts to predict and data-mine potential side effects. We still have a lot to learn, in case anyone had any doubts.
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