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February 12, 2006
Kinase Inhibitors: Doomed From the Start?
Gilbert Rishton, ex-Amgen and now with an Alzheimer's institute in academia, sent along this paper the other day (PDF) which is worth a look for anyone in our business. Titled "Failure and Success in Modern Drug Discovery", it's a very opinionated look at the subject.
I sent it around in my department at the Wonder Drug Factory, and reactions were strong and all over the map. Several people found it right on target (and rather refreshing) while others were more reserved or outright hostile. One of the more controversial sections contends that drug discovery efforts are seriously overweighted in kinase inhibitors because the compounds are likely to be intrinsically toxic via general signal transduction inhibition in non-target organs. I'm pretty sure that I buy the first part, but I'm not sure about the second.
I think that the big problem in kinase inhibition is that we don't understand the details of the biochemical pathways anywhere near well enough in most cases. So we look at the state of the art and say "Well, it's clear that XYZ kinase is a key player in this pathway, so let's go inhibit it". But if we do, likely as not we find that there are so many compensating mechanisms that inhibiting XYZ hardly does anything. But that's if we have a selective compound, mind you. Most of the time we're hitting enough other kinases that it's impossible to say just what's causing any particular in vivo effect.
Anyway, take a look at the article and feel free to post comments that you might have. There's something in it to offend almost everyone. I'll be returning to some of its themes in later posts. . .
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