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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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February 5, 2007

Good Mistakes?

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Posted by Derek

Here's an interesting press release on a potential new class of anticancer drugs. It has a nice hook ("Lab mistake leads to cancer finding!"), and the work itself isn't bad at all. It's an neat biochemical result, which might eventually lead to something. You have to know a bit about drug discovery and development to spot the problem, though - and not that many people do, which provides the ecological niche for this whole blog, frankly.

The discovery (from the University of Rochester) has to do with PPAR-gamma compounds, an area of research I've spent some time in. I didn't spend enough time there to understand it, mind you - no one has spent enough time to do that yet, no matter how long they've been at it. I wrote about some of the complexities here in 2004, and things have not become any more intelligible since then. The PPARs are nuclear receptors, affecting gene transcription when small molecules bind to them. There are, however, zillions of different binding modes in these things and they affect a list of genes that stretches right out the door. Some get upregulated, some down, and these vary according to patterns that we're only beginning to understand.

The Rochester group found that a particular class of compounds, the PPAR-gamma antagonists, had an unexpected toxic effect on some tumor cell lines. Their tubulin system was disrupted - that's a structural protein which is very important during cell division, and is the target for other known oncology drugs (like Taxol). The PPAR ligands seem to be messing with tubulin through a different route than anyone's seen before, though, and that definitely makes it worth following up on.

But the tone of the press release is too optimistic. (I should turn that line into some sort of macro, since I could use it twenty times a day). It mentions "high-dose" PPAR antagonist therapy as a possible cancer treatment, but take a look at the concentrations used: 10 to 100 micromolar. Even for cells in a dish, that's really hammering things down. And there's hardly any chance that you could attain these levels in a real-world situation, dosing a whole animal (or human). As blood levels go, those are huge.

But how about using more potent compounds? Of the three that are mentioned in the paper, BADGE is pretty dead, but the other two are actually quite potent. Tellingly, nothing happened at all with any of them up to 1 micromolar. These things will mess with other PPAR-gamma driven processes at much lower concentrations, so you have to wonder what's really going on here. And keep in mind that other PPAR compounds whose mode of action is roughly the opposite of these have been suggested as potential anticancer agents, too - this sort of thing happens all the time with nuclear receptors, and reflects their head-grabbing complexity.

This is still worth figuring out; don't get me wrong. There might be a new mechanism here that could lead to something, eventually, although it looks to be a tough problem. But that's the part of this work that's interesting - the level of activity seen here isn't. If I had a dollar for every compound that affects tumor cells at 50 micromolar, I wouldn't need to be sending my CV out these days.

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


1. TNC on February 6, 2007 11:50 AM writes...

A question perhaps too complicated for this space: what is the 'magic' concentration number that's just too high to be a likely clinical candidate? Is it 100 micromolar?

I know it's not something that can be easily answered, but it's reasonable that no one wants to take horse pills of drug.

I know that in the early days of protease inhibitors, people needed to take pills constantly (to keep their blood levels of inhibitor up?) I'm guessing that had something to do with potency, but I dunno.

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2. Anonymous on February 6, 2007 1:25 PM writes...

The protease story had less to do with potency and more to do with the terrible pk of these compounds. This is typical of aspartyl protease inhibitors as they tend to be more peptidic. Recently, efforts on beta-secretase and renin have led to less peptidic looking aspartyl protease inhibitors.

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3. Joseph on February 6, 2007 4:24 PM writes...

I know at my company the highest concentration we even test anti-cancer compounds is 30 micromolar. If its IC50 is >30 micromolar its considered to have no significant activity. We get interested when the IC50s drop below 100 nM and have some compounds in the

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4. Ken on February 6, 2007 5:43 PM writes...

Derek - read the paper again. It clearly states that the effects have NOTHING to do with PPAR-gamma. The two compounds that kill the cancer cells are alkylating agents (that's how they block PPAR activity, by reacting with a cysteine in the receptor). I would suspect that any alkylating agent at 100uM would kill the cells!

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5. david on February 7, 2007 12:31 AM writes...

The problem with this sort of compound is the likely neurotoxicity. That's the problem with the taxanes. Neurons need the proper functioning of microtubules if they are going to perform. Take them away and you may kill the cancer, but the patient sans chunks of his/her peripheral nervous system, may prefer dealing with the cancer instead of the side effect. There will need to be a lot more work before such compounds ever get into the clinic. Danger Will Robinson.

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