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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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August 11, 2005

Selectivity: One of Those Flexible Concepts

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Posted by Derek

One of the comments to the last post mentioned that a way to provide the benefits of a combination therapy is to make a drug that hits more than one target. For a while there, this idea was a bit out of fashion, but I think it's been making a comeback.

There are a number of multiple-target drugs on the market already, and the list even includes some where this profile was arrived at deliberately. (That was a joke. I think.) Examples of the planned category include Tracleer (bosentan), a dual endothelin receptor antagonist for pulmonary hypertension, rupatadine, a dual histamine/PAF antagonist for allergy (not yet approved in the US, I think), and Cymbalta (duloxetine), an antidepressant which affects both serotonin and noradrenaline reuptake.

Examples of the non-deliberate class include all sorts of drugs marketed before the 1980s or so. (That's about the time that target-based drug design really took over, as opposed to "see what it does in vivo".) In some therapeutic classes, this is the norm - the activities of CNS drugs in general are known to be extraordinarily messy. The antipsychotics, for example, hit so many receptors that it's basically impossible to figure out just how they work. A more recent example is the cardiovascular drug Pletal (cilostazol), which is both a PDE-III inhibitor and an adenosine uptake inhibitor. Other PDE-III inhibitors didn't work nearly as well, so there was clearly something else pitching in. (There may well be something similar at work with Lipitor, to pick a drug that everyone's actually heard of, although no one's quite sure what the extra activity is.)

There are all sorts of other dual-acting drugs being looked at in earlier phases of development. For the most part, they're going after similar receptor subtypes or related enzymes, since that's where you're most likely to get the cross-reactivity. (A good example would be the PPAR alpha-gamma ligands that many companies have been trying to develop for diabetes.) But the biggest area of multiple-action drugs now is cancer.

You might not know it from reading the popular press, though. A lot of reporters are still a generation behind, going on about the new breed of incredibly selective targeted cancer drugs. Problem is, it's turning out that some of those incredibly selective drugs work only on incredibly small numbers of cancer patients, which is not what everyone had in mind. Over the last few years, efforts have shifted to making drugs that hit a slew of potential cancer targets simultaneously, in hopes that this will show more efficacy, and these are just coming to the FDA now.

Many, many cancer targets are from a large family of broadly similar enzymes (the kinases), so getting multiple activities isn't really all that hard. In fact, getting selective kinase inhibitors was the hard part - looking back, had we but known, we all could have probably skipped that step and gone right to the blunderbusses. But the fear was that these compounds would be too toxic (yeah, even for cancer therapy), so selectivity got priority. Now that it turns out that we don't need to be so picky, it's also becoming clear that the multiple-kinase drugs are tolerated a lot better than we thought. You'll see the word "targeted" thrown around when these agents are discussed, but it should have quotes around it.

Comments (7) + TrackBacks (0) | Category: Cancer | Cardiovascular Disease | Drug Development


1. zp2k on August 11, 2005 11:16 PM writes...

How is the FDA responding to this sort of thing? Naively, I would have guessed that it would be a lot harder to get IND approval for drugs without single-target specificity.

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2. GA on August 12, 2005 9:25 AM writes...

Not just cancer...for indications like inflammation as well, where several kinase cascades contribute, people are starting to think that selectivity might actually be a bad thing. Although the "acute" vs "chronic" debate really makes this tough to argue for a less selective kinase inhibitor for inflammation.

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3. linus on August 12, 2005 10:36 AM writes...

I'm new here - first stopped by after I read about this blog in Science. Lots of interesting thoughts, Derek. I'm a biologist, worked in Big Pharma for >20 years, in antibacterial discovery, and am now doing independent consulting. About dual (or more) targeted drugs: Its interesting to note that all of the clinically useful systemic monotherapeutic antibacterials have multiple targets. Most likely because the likelihood/frequency of resistance development through target mutation is greatly reduced. Discovery efforts are finally taking note of this and dual/multiple target inhibitors are gaining favor in antibacterials as well.

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4. PsychicChemist on August 12, 2005 1:29 PM writes...

A vast majority of antibacterials kill bacteria, either by inhibiting protein synthesis (by interfering with the translation machinery, or by inhibiting cell wall biosynthesis. So even if you are specifically inhibiting the translation machinery, as a consequence of that, you are affecting all the proteins being synthesized in the cell. I wonder if anyone has tried this sort of approach (ie non specific eukaryotic protein synthesis inhibitors) in oncology - The challenge of course, would be to deliver these agents selectively to tumor cells.

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5. Derek Lowe on August 12, 2005 2:24 PM writes...

As I understand it, the therapeutic window has been a problem with going after protein synthesis. It's active through so much of the cell cycle, as compared to the DNA targets, that you'd expect problems. Still, it is being worked on. And since no one thought that another hard-core protein mechanism, Millennium's Velcade (a proteosome inhibitor) would make it, maybe there's some hope.

Some of the DNA-interacting agents are thought act at least partly through disrupting protein synthesis downstream, although it's mighty hard to prioritize chickens and eggs in these mechanisms.

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6. Peter Ellis on August 13, 2005 4:52 AM writes...

The challenge of course, would be to deliver these agents selectively to tumor cells.

Hmmm, well, yes. If you had a magic delivery system that only ever delivered your stuff to cancer cells, then there's no need to be specific at *all*, just use bleach.

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7. PsychicChemist on August 13, 2005 2:37 PM writes...

I have read some recent literature regarding tumor targeting technologies and it appears that people are making some progress in this area. A good example would be Mylotarg (Calicheamicin linked to a tumor targeting antibody, via an acid labile linker that falls apart in the endosome). I would think that these sort of approaches will become more important if "less selective" anti-cancer agents are the way to go. In any case, I dont think bleach will work (I understand the pun) as it will probably react with any type targeting agent you might want to use - especially if your targeting agent happens to be a bio-macromolecule of some type. But if you still like bleach, an option would be to encapsulate it in some funky carbon nano-tube (lined with a nano layer of steel perhaps) that miraculously reaches and liberates bleach selectively in tumor cells. And, of course, you can refer to any recent issue of JACS as to how to make this miracle molecule.

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