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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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June 19, 2005

What Makes A Target, Anyway?

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Posted by Derek

I had a question a while back about how often researchers are fooling themselves when they think they've found a new signaling pathway or a new disease target. That one's pretty easy to answer, to a rough approximation: the less work you do, the better the chance that you're fooling yourself.

But it can take years before you know if you were right, so there's really not enough data to give a more quantitative answer. Take a notorious example, beta-amyloid in Alzheimer's disease. That's been noted as a sign of the disease every since Alois Alzheimer described it nearly one hundred years ago. Huge mountains of data have piled up since then about the disease and what might be causing it, but we're still not one hundred per cent sure if amyloid plaques in your brain give you Alzheimer's or if Alzheimer's gives you amyloid plaques in your brain. Most of the money is on the former, but it's not quite a sealed case yet.

The same uncertainty hovers around everywhere. Let's say you study a particular form of cancer, and you find that there's a particular kinase that's always found in greater than normal amounts in the tumor cells as compared to normal ones. Is that a new target for therapy? The answer is a firm, resounding, "maybe!"

Perhaps it's the real deal, but there are other enzymes that will step right in to do your kinase's job if you inhibit it - in that case, you'd better be prepared to take those on, too, or get ready to pack it in. Perhaps it's part of the real problem, but it's just a sideshow. If it's not the key or limiting step in any given pathway, inhibiting it won't do anyone much good. Or maybe it's there to phosphorylate the realculprit, in which case you should put some resources on tracking that thing down, too - it could be a better handle on the disease. But on the other hand, maybe your kinse is only acting downstream of that real culprit, phosphorylating something else entirely, which is an extreme example of the sideshow possibility mentioned above. Or it may be that this kinase is upregulated because it's part of a mechanism that's trying (unsuccessfully) to get the cancer cell to shut down. You probably wouldn't want to inhibit that!

Unraveling all this is not a job for the impatient, or for the light of wallet either, for that matter. So many of these pathways have turned out to be more complicated than anyone had ever imagined, that it's gotten to the point that people are questioning the whole reductionist-molecular-biology approach to drug targets. Eight or ten years ago, I would have considered that a radical or even crazy position. These days, I kind of want to sign up. . .

Comments (6) + TrackBacks (0) | Category: Drug Assays


1. BrianF on June 20, 2005 1:29 PM writes...

"questioning the whole reductionist molecular bioloby appproach to drug targets." Any links to plausible alternate hypothesis of drug action?

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2. brianf on June 20, 2005 1:50 PM writes...

Was not combi-chem the chemist response to the rise of molecular biological targets (novel target no lead....combi!!!) Their rise coorelates with the decline in the number of new drugs and general drought in pharma. It seems the new approach is much more theoretical and dependant on us thinking we know what is going on while the old approach was more empirical and less theoretical. it is as if the roles reversed. THe chemists no longer used med chem knowledge but went with the numbers, while the biologists scrapped the old black box clinical assays for more nuanced in vitro assays. Possibly it was molecular biology reductionist target strategy that has mislead us and not combi by simply created more hurdles and useless data than any science group can wade through on the way to the market.

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3. Derek Lowe on June 20, 2005 3:04 PM writes...

Oh, it's not that drugs don't work through targets. It's just that we don't seem to be very good at unraveling what they are. And some of those targets are probably polypharmacological, playing a chord instead of a single note. I'll post some recent references as soon as I can dig 'em out of my files.

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4. Dr Snowboard on June 21, 2005 3:12 AM writes...

Didn't 'Dr Paul' Janssen say quite a few years ago (and perhaps presciently) that 'all the easy targets had gone'? It may be a simplification but the shift from extracellular / TM targets to looking at intracellular / nuclear pathways may also account for the efficiency 'drop'. To re-use somebody else's analogy, building a bigger haystack doesn't make drug discovery any easier. ..

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5. daen on June 21, 2005 7:55 AM writes...

As far as I understand it, the interdisciplinary approach suggested by systems biology could provide a way to give answers to some of the points you raise, Derek. (

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6. Derek Lowe on June 21, 2005 9:19 AM writes...

Systems biology is definitely a response to these worries (both the problems of drug discovery and worries about the reductionist approach in general.) I was talking with one of my colleagues about it the other day, though, and he pointed out that right now, the best working definition of "systems biology" is "something that we can get funded for." I guess every field goes through that stage. . .

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