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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: derekb.lowe@gmail.com Twitter: Dereklowe

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January 29, 2010

Johnson May Have Been On to Something

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Posted by Derek

The crew at Angewandte Chemie has produced another head-shaking pun in one of their latest abstracts. Read only if (1) you know your 1980s music, and (2) you have a high tolerance for wordplay. When I was in Germany, this sort of joke was known as an "eiskalter" and was greeted with shivers.

Comments (10) + TrackBacks (0) | Category: The Scientific Literature

Merck and Sirna

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Posted by Derek

Xconomy has a look inside the Merck-Sirna acquisition, an interview with Merck's head of that area. As you'd guess, he emphasizes that one of the biggest challenges in the field is delivery, and he makes the pitch that this is how Merck is going to make this work out:

What you often read about, but many people don’t understand, is how hard it is to make a drug. Our approach to RNA Therapeutics is made with a recognition of the full package it takes to launch a successful commercial product. . .That’s versus another strategy you see from smaller companies, which is to get an interesting experimental result, and publicly disclose it in an attempt to increase the value of your investment or a VC’s investment, without a real [awareness] of what it will take to make a therapeutic eight years later. . .

We immediately, after the acquisition, invested not just heavily in the RNA piece that is here in San Francisco, but we built an entire delivery group in West Point, PA. The thing that continues to differentiate Merck is that we have people with decades of experience in pharma R&D, drug safety, metabolism, pharmacokinetics. . .

Outside of RNA as a therapy in itself, he also talks about Merck's use of the technology to better understand its small-molecule targets. It's not something that you'll ever see press releases about, but trustworthy data of that sort is very useful and important. As the Xconomy interviewer notes, Wall Street values this sort of thing as basically zero (partly because you can't see the results of it for quite a while, if they're ever made public at all), but the value inside the company can be significant.

Of course, there can be things that happen inside drug companies that significantly destroy value, too, and it's not like the stock market can see (or understand) many of those, either, but that's a topic for another post entirely. . .and on a not perhaps unrelated note, one part of the interview above seems to suggest that "POS" is an internal Merck acronym for. . .wait for it. . ."probability of success". I, uh, kid you not.

Comments (6) + TrackBacks (0) | Category: Business and Markets | Drug Assays | Drug Development

Sure Thing

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Posted by Derek

I get a lot of press releases around here - not a day goes by that several don't show up in the e-mail queue. I glance over the titles, and I'll open up the more interesting ones and look at them in more detail. Since I feel no obligation to read unsolicited bulk mail (who does?), the less interesting ones get deleted without opening.

Most of what shows up is reasonably well targeted, from university press offices or scientific publishers, and once in a while one of them will lead to a blog post. The PR from small pharma/biotech companies is also probably well targeted, but it's much less likely to lead to anything, simply because there's so much of that stuff around and because it tends, on the average, to be decidedly less interesting: "Spamozyme, Inc. announces its new ZippyChip assay, now with the great taste of fish!" (I don't have the heart to ask Google if "ZippyChip" is the name of a real technology; I fear the answer).

But I also get things that are seriously misguided. Publicists ask me if I want to talk to someone who's just published "Nineteen All-Natural Ways to Quantum Healing" or some damn thing, and the answer is, no, of course I don't. I'd rather drop an Erlenmeyer flask on my foot. Come to that, I'd rather read press releases about the ZippyChip. I know somebody's getting value for their publicity dollar when I get an e-mail pitch asking if my readers would be interested in learning the ways to holistic health without resorting to dangerous and toxic pharmaceuticals

Comments (4) + TrackBacks (0) | Category: Blog Housekeeping

January 28, 2010

Your First Pharma Bloodletting of 2010: AstraZeneca

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Posted by Derek

As many had feared, AstraZeneca used their announcement of financial results as the cue to also announce another round of layoffs. I'd been hearing word that this might be coming, but didn't have a line on the size and timing. But it's 8,000 jobs over the next four years, and that Chemistry World link says that 1,800 of them will be in R&D. Another 1,700 R&D jobs will be affected as people and departments move around.

AZ has plenty of patent trouble coming (Crestor's expiration foremost), and plenty of legal bills. So I wouldn't necessarily say that today's announcement will end the layoff process, either, unfortunately. . .

Comments (23) + TrackBacks (0) | Category: Business and Markets

A Scorched-Earth Policy at Wyeth's Princeton Site?

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Posted by Derek

This information comes to me secondhand, so I'm not sure how accurate it is. I hope it turns out not to be true. A correspondent writes to me that he's spoken this week to someone who had recently been at the former Wyeth site in Princeton, which is in the process of shutting down. The usual practice is for industrial research sites to make surplus equipment available to academic labs and the like, but the report is that this isn't happening in this case.

Instead, glassware is just being broken and tossed, along with a lot of other equipment, and the entire chemical reagent collection is supposedly going to be carted off by a waste disposal firm for incineration. That must be the commercially available stuff on the shelves - sometimes it's not worth the paperwork and trouble to send those on somewhere else, but sometimes it is. But the glassware and equipment definitely shouldn't be going to waste, but from the sound of this report, that's just what's happening.

Can anyone add details to this? Are the people closing down that site really just heaving everything into dumpsters?

Comments (31) + TrackBacks (0) | Category: Current Events

Acorda and Ampyra

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Posted by Derek

I had not been following the progress of Acorda's recently approved drug Ampyra for MS. (Well, more specifically, it's to improve gait and walking speed in MS patients). Opinion seems to be rather divided about how successful it'll be. On the one hand, new therapies for multiple sclerosis are certainly needed, but there's also room to argue about just how efficacious Ampyra really is.

I'm not going to fight that one out here, because we'll have the judgment of the market pretty soon. What I find interesting is the structure of this new drug: it's 4-aminopyridine. If there's a more simple, lower molecular weight structure approved within the next few years as an oral drug for anything, I'll be quite surprised.

This brings up several interesting topics relating to drug development and intellectual property. For one thing, this compound has been known for many years as a ligand for neuronal voltage-gated potassium channels, which is the mechanism by which it seems to work for MS patients. Some of these patients have experimented with it themselves over the years; the idea of using it for multiple sclerosis is certainly not new. (Here's a good history, taking things back a good 30 years through many players, with Elan a prominent one).

Secondly, it's not like the compound's chemical structure can be patented as such, either, since it's nowhere near novel. I have no idea of when 4-aminopyridine first makes its appearance in the chemical literature, but it's surely back into the 19th century. Nor is it anything like a rare chemical. For many years it was used as a bird-control poison. (High doses are fatal, but lower ones cause bird seizures that cause the rest of the flock to leave in consternation). We've got some on the shelf in our stockroom; I see in my Aldrich catalog that they're selling the 99% grade for $18/gram. And Aldrich is not exactly the world's low-cost chemical supplier. A railroad car full of the stuff could surely be arranged through someone, although it wouldn't exactly be pharmaceutical grade.

So. . .how then, some might wonder, does Acorda Therapeutics (partnered with Biogen Idec) get to charge several thousand dollars a year for Ampyra? (I don't think the actual price is known yet, but that's the best guess I've seen). One key factor is the bird-repellant aspect. Messing with ion channels in nerves is a tricky business, and 4-aminopyridine can and will cause trouble in humans if it's not dosed carefully. It's also (I believe) cleared pretty quickly, as you'd expect from something with that structure. Ampyra is a time-release formulation, an attempt to get enough of the compound into circulation over a long enough period, but without crossing over the line to too high a concentration, which could set off seizures and worse. Taking 4-aminopyridine from that railroad car and using that instead would be very much not recommended, considering what's waiting out there at inappropriate doses.

And that's Acorda's intellectual property. Plenty of work was done to find a good formulation for the drug, and Acorda spent the time and money to test one for safety and efficacy. They get to reap the fruits of their labors, if fruits there are. And that's what the market will decide for them. . .

Comments (28) + TrackBacks (0) | Category: Patents and IP | The Central Nervous System

January 27, 2010

Enzymes and Fluorines

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Posted by Derek

It hit me, one day during my graduate career, that I was spending my nights, days, weekends, and holidays trying to make a natural product, while the bacterium that produced the thing in the first place was sitting around in the dirt of a Texas golf course, making the molecule at ambient temperature in water and managing to perform all its other pressing business at the same time. This put me in my place. I've respected biosynthesis ever since.

But there are some areas where we humans can still outproduce the small-and-slimies, and one of those is in organofluorine compounds. Fluorine's a wonderful element to use in medicinal chemistry, since it alters the electronic properties of your molecule without changing its shape (or adding much weight), and the C-F bond is metabolically inert. But those very properties can make fluorination a tricky business. If you can displace a leaving group with fluoride ion to get your compound, then good for you. Too often, though, those charges are the wrong way around, and electrophilic fluorination is the only solution. There are heaps of different ways to do this in the literature, which is a sign to the experienced chemist that there are no general methods to be had. (That's one of my Laws of the Lab, actually). The reagents needed for these transformations start with a few in the Easily Dealt With category, wind entertainingly through the Rather Unusual, and rapidly pile up over at the Truly Alarming end.

But at least we can get some things to work. The natural products with fluorine in them can be counted on the fingers. A fluorinase enzyme has been isolated which does the biotransformation on 4-fluorothreonine S-adenosyl methionine (using fluoride ion, naturally - if an enzyme is ever discovered that uses electrophilic F-plus as an intermediate, I will stand at attention and salute it). And now comes word that this has been successfully engineered into another bacterial species, and used to produce a fluorine analog of that bacterium's usual organochlorine natural product.

It isn't pretty, but it does work. One big problem is that the fluoride ion the enzyme needs is toxic to the rest of the organism, so you can't push this system too hard. But the interest in this sort of transformation is too high (and the potential stakes too lucrative) to keep it from being obscure forever. Bring on the fluorinating enzymes!

Comments (11) + TrackBacks (0) | Category: Biological News

Sequenom: Strike Up the Music, Bring On the Cream Pies

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Posted by Derek

Now here's a weird one. The San Diego diagnostics company Sequenom came up with a non-invasive test for Down's Syndrome, and sold it to another outfit, Xenomics, for development. Update: I've got this transfer backwards - Xenomics licensed some of its nucleic acid technology to Sequenom, and has now regretted it. But late last year, things unraveled spectacularly. In April, Sequenom announced that there were problems with the test and announced that it had launched an internal investigation. In September came the unwelcome news that the data backing up their product were (quoting here) "inadequately substantiated". And they meant it, too, as the CEO and six other higher-ups all left the company under a cloud of confusion, recrimination, and very bad acronyms (like SEC and FBI). Last week it settled a dozen shareholder lawsuits over the whole affair.

But as that story at Bnet makes clear, the terms of the settlement were rather alarming, with Sequenom promising to do things like. . .make sure that everyone involved knew which studies were blinded and which weren't. And requiring bar-codes on the tissue sample vials. And not giving everyone access to the storage room where they were all kept. And. . .well, you get the idea. It's like seeing a sign at the burger place that says "Healthy Choice - Now With 30 Per Cent Less Aardvark Meat! And Try Our New No-Salmonella Menu!"

It can always get worse, though. Now Xenomics is suing, claiming that not only were the data weak and the controls insufficient, but that there never was a test in the first place. The complaint (available as a PDF at that link) is pretty zippy stuff by legal standards, featuring phrases such as "Defendant maintained the charade that it had. . ."

Way before all this lunacy, some people were skeptical about the company's prospects even if things went well. But hey, let's not dwell on the negatives here. If you'd like "Three Reasons to Buy Sequenom Today", this guy has them. I think I'll let this opportunity slip past, personally.

Comments (20) + TrackBacks (0) | Category: Analytical Chemistry | Business and Markets | The Dark Side

January 26, 2010

A Storm in a Teacup

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Posted by Derek

So says GlaxoSmithKline CEO Andrew Witty about the Sirtris controversy - see this Forbes story for more. I hope he's right. I actually would like to see good things come out of sirtuin research - the biology's clearly interesting enough. And I would like to think that GSK didn't blow $720 million, because we could all use that sort of money these days. This story will only be settled for sure in the clinic, with the agents the GSK is developing. Good luck to them. I fear that they might need it, but I hope that they don't.

Comments (14) + TrackBacks (0) | Category: Aging and Lifespan

The Infinitely Active Impurity

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Posted by Derek

Yesterday's post touched on something that all experienced drug discovery people have been through: the compound that works - until a new batch is made. Then it doesn't work so well. What to do?

You have a fork in the road here: one route is labeled "Blame the Assay" and the other one is "Blame the Compound". Neither can be ruled out at first, but the second alternative is easier to check out, thanks to modern analytical chemistry. A clean (or at least identical) LC/MS, a good NMR, even (gasp!) elemental analysis - all these can reassure you that the compound itself hasn't changed.

But sometimes it has. In my experience, the biggest mistake is to not fully characterize the original batch, particularly if it's a purchased compound, or if it comes from the dusty recesses of the archive. You really, really want to do an analytical check on these things. Labels can be mistaken, purity can be overestimated, compounds can decompose. I've seen all of these derail things. I believe I've mentioned a putative phosphatase inhibitor I worked on once, presented to me as a fine lead right out of the screening files. We resynthesized a batch of it, which promptly made the assay collapse. Despite having been told that the original compound had checked out just fine, I sent some out for elemental analysis, and marked some of the lesser-used boxes on the form while I was at it. This showed that the archive compound was, in fact, about a 1:1 zinc complex, for reasons that were lost in the mists of time, and that this (as you can imagine) did have a bit of an effect on the primary enzyme assay.

And I've seen plenty of things that have fallen apart on storage, and several commercial compounds that were clean as could be, but whose identity had no relation to what was on their labels (or their invoices for payment, dang it all). Always check, and always do that first. But what if you have, and the second lot doesn't work, and it appears to match the first in every way?

Personally, I say run the assay again, with whatever controls you can think of. I think at that point the chances of something odd happening there are greater than the chemical alternative, which is the dreaded Infinitely Active Impurity. Several times over the years, people have tried to convince me that even though some compound may look 99% clean, that all the activity is actually down there in the trace contaminants, and that if we just find it, we'll have something that'll be so potent that it'll make our heads spin. A successful conclusion to one of these snipe hunts is theoretically possible. But I have never witnessed one.

I'm willing to credit the flip side argument, the Infinitely Nasty Impurity, a bit more. It's easier to imagine something that would vigorously mess up an assay, although even then you generally need more than a trace. An equimolar amount of zinc will do. But an incredibly active compound, one that does just what you want, but in quantities so small that you've missed seeing it? Unlikely. Look for it, sure, but don't expect to find anything - and have 'em re-run that assay while you're looking.

Update: I meant to mention this, but a comment brings it up as well. One thing that may not show up so easily is a difference in the physical form of the compound, depending on how it's produced. This will mainly show up if you're (for example) dosing a suspension of powdered drug substance in an animal. A solution assay should cancel these things out (in vitro or in vivo), but you need to make sure that everything's really in solution. . .

Comments (33) + TrackBacks (0) | Category: Analytical Chemistry | Drug Assays | Life in the Drug Labs

January 25, 2010

GSK and Sirtris: A Bit More

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Posted by Derek

Nature has a short item on the Pfizer paper that questions the reproducibility of some key sirtuin work (covered here and here). There are some good points to temper the pessimism. Leonard Guarente of MIT, a key pioneer in the field, says:

". . . that the latest findings are neither surprising nor worrisome. The compounds may work only with fluorophore-conjugated peptides in vitro, says Guarente, but the situation is different in cells and in animals. The Nature paper, among others, went beyond the test tube and indicated that SIRT1 was more active in cells and in animals after application of the Sirtris compounds. Furthermore, resveratrol administration made no difference to the lifespan of yeast that did not have Sir23, indicating that the compound's action depends on this gene.

According to a statement from GlaxoSmithKline, Ahn's conclusion "ignores any possibility of direct activation of SIRT1 that may occur in a cellular environment that is not reproduced in vitro".

True, but there's still that problem of the Pfizer group not being able to reproduce the in vivo effects, which to me was perhaps the most worrisome part of the paper. Now, it's worth remembering that animal studies are not the easiest things in the world to do right, since there are so many variables. Small differences in animal strains and the like can sometimes throw things off severely. Even the Pfizer group admits this readily, with Kay Ahn telling Nature that "every in vivo experiment is a little bit different" and that "Under our conditions we didn't see beneficial effects, but we don't want to make a big conclusion out of those results."

That's an honorable way to put things, I have to say. Rather less honorable, though, at least to me, is David Sinclair's response from the Sirtris team. See what you think:

A possible explanation for the discrepancy, says Sinclair, is that Ahn and her colleagues did not provide information on the characterization of the compounds, which they synthesized themselves. So there is no way of knowing how pure they were or whether they're the same as those made by Sirtris. "The fact that mice died indicates that there may be an issue with purity,"
.

That's. . .not so good. In fact, it comes close to being insulting. Although I say a lot of uncomplimentary things about Pfizer's management, the fact remains that they have a lot of very good scientists there. And I assume that they can reproduce Sirtris's published procedures to make the sirtuin ligands. If they can't, frankly, that's Sirtris's fault. Everyone (well, everyone competent) checks out compounds thoroughly before putting them into an animal study. Asking "Are you sure you made the right stuff?" at this point is really a bit much, and doesn't do anything improve my opinion of Sirtris. (Which opinion actually was pretty good - until recently).

Comments (40) + TrackBacks (0) | Category: Aging and Lifespan | Drug Assays

January 22, 2010

Receptors, Moving and Shaking

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Posted by Derek

I've written here before about how I used to think that I understood G-protein coupled receptors (GPCRs), but that time and experience have proven to me that I didn't know much of anything. One of the factors that's complicated that field is the realization that these receptors can interact with each other, forming dimers (or perhaps even larger assemblies) which presumably are there for some good reason, and can act differently from the classic monomeric form.
M1%20receptors.jpg
A neat paper has appeared in PNAS that gives us some quantitative numbers on this phenomenon, and some great pictures as well. What you're looking at is a good ol' CHO cell, transfected with muscarinic M1 receptors. Twenty years ago (gulp) I was cranking out compounds to tickle cell membranes of this exact type, among others. The receptors are visualized by a fluorescent ligand (telenzepine), and the existence of dimers can be inferred by the "double-intensity" spots shown in the inset.

With this kind of resolution and time scale, the UK team that did this work could watch the receptors wandering over the cell surface in real time. It's a classic random walk, as far as they can tell. Watching the cohort of high-intensity spots, they can see changes as they switch to lower-intensity monomers and back again. Over a two-second period, it appeared that about 81% of the tracks were monomers, 9% were dimers, and 3% changed over during the tracking. (The remaining 7% were impossible to assign with confidence, which makes me wonder what's lurking down there).

They refined the technique by using two differently-fluorescent forms of labeled telenzepine, labeling the cells in a 50/50 ratio, and watching what happens to the red, green, (and combined yellow) spots over time. It looks as if the receptor population is a steady-state mix of monomers and dimers, exchanging on a time scale of seconds. Of course, the question comes up of how different ligands might affect this process, and you could begin to answer that with different fluorescent species. But since the technique depends on having a low-off-rate species bound to the receptor in order to see it, some of the most interesting dynamic questions will have to wait. It's still very nice to actually see these things, though; it gives a medicinal chemist something to picture. . .

Comments (7) + TrackBacks (0) | Category: Biological News

Maybe You Need Some More Testosterone Over There

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Posted by Derek

This one's also from the Department of Placebo Effects - read on. An interesting paper out in Nature details a study where volunteers took small doses of testosterone or placebo, and then participated in a standard behavioral test, the "Ultimatum Game". That's the one where two people participate, with one of them given a sum of money (say, $10), that's to be divided between the two of them. The player with the money makes an offer to divide the pot, which the other player can only take or leave (no counteroffers). A number of interesting questions about altruism and competition have been examined through this game and its variants - basically, the first thing to ask is how much the "dictator" player will feel like offering at all. (If you like, here's the Freakonomics guys talking about the game, which features in a chapter of their latest, SuperFreakonomics).

What's been found in many studies is that the second players often reject offers that they feel are insultingly low, giving up a sure gain for the sake of pride and sending a message to the first player. I think of this as the "Let me tell you what you can do with your buck-fifty" option. So what does exposure to testosterone do for this behavior? As the authors of the new paper talk about, there are two (not necessarily exclusive) theories about some of the hormone's effects. Increases in aggression and competitiveness are widely thought to be one of these, but there's also a good amount of literature to suggest that status-seeking behavior is perhaps more important. But if someone is going to be aggressive about the ultimatum game, they're going to make a lowball offer and damn the consequences, whereas if they're looking for status, they may well choose a course that avoids having their offer thrown back in their face.

Using known double-blind conditions for testosterone dosing in female subjects (sublingual dosing four hours before the test), the second behavior was observed. Update: keep in mind, women have endogenous testosterone, too. The subjects who got testosterone made more generous offers (from about $3.50 to closer to $4.00). The error bars on that measurement just miss overlapping, p = 0.031. But here's the part I found even more interesting: the subjects who believed that they got testosterone made significantly less fair/generous offers than the ones who believed that they got the placebo (P = 0.006). Because, after all, testosterone makes you all tough and nasty, as everyone knows. As the authors sum it up:

"The profound impact of testosterone on bargaining behaviour supports the view that biological factors have an important role in human social interaction. This does, of course, not mean that psychological factors are not important. In fact, our finding that subjects’ beliefs about testosterone are negatively associated with the fairness of bargaining offers points towards the importance of psychological and social factors. Whereas other animals may be predominantly under the influence of biological factors such as hormones, biology seems to exert less control over human behaviour. Our findings also teach an important methodological lesson for future studies: it is crucial to control for subjects’ beliefs because the pure substance effect may be otherwise under- or overestimated. . ."

Comments (13) + TrackBacks (0) | Category: Biological News | General Scientific News | The Central Nervous System

January 21, 2010

An Enzyme Inhibitor You Have Never, Ever, Considered

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Posted by Derek

I promise you that. Take a look at this abstract:

". . .an unappreciated physicochemical property of xenon has been that this gas also binds to the active site of a series of serine proteases. Because the active site of serine proteases is structurally conserved, we have hypothesized and investigated whether xenon may alter the catalytic efficiency of tissue-type plasminogen activator (tPA), a serine protease that is the only approved therapy for acute ischemic stroke today."

They go on to provide evidence that xenon is indeed a tPA inhibitor. And as it turns out, there's more evidence for xenon having a number of physiological effects, and enzyme inhibition has been proposed as one mechanism. Who knew?

Now, there's an SAR challenge. . .

Comments (19) + TrackBacks (0) | Category: Biological News

In Hoc Signo Non Vinces

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Posted by Derek

I am here to confess to a deep-seated prejudice, one that has been with me for many years now. I know that others feel differently, but I'm sticking to my rule: No Naphthyls.

OK, pile on me now for having a closed mind. I know that there are drugs that are more successful than anything I'll ever make that have a naphthalene in them. (At least that structure's a small one). It's just that I see a naphthyl as the worst sort of "potency through greasiness" move in drug design. They hurt your solubility, drive up your molecular weight, open you to metabolites that you may not care for, and all for what? A little activity in your in vitro assay.

I'm getting close to putting cyclohexyl on the same list, if you want to know the truth. Problem is, people make these things "just as SAR compounds". You know, they'll trowel this hunk of grease onto the side of the molecule, just to see what happens, and if it really looks good, well, they'll. . .find some way to make it better. Right. Tetrahydropyranyl instead, that'll do it. But my attitude is, why not just make the THP derivative in the first place, if that's where you're going to go?

SAR is long, and life is short. There isn't time to make everything. So I decided a long time ago that I'd try to only make structures that I could live with. That still admits a lot of weird stuff, don't get me wrong. I have functional groups on my go-to lists that make people roll their eyes. But I draw the line at flat slabs of lard. No naphthalenes.

Comments (25) + TrackBacks (0) | Category: Life in the Drug Labs

January 20, 2010

A Database of Side Effects

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Posted by Derek

There's probably a lot of undiscovered information sitting out there in clinical trial data sets. And while I was just worrying the other day about people with no statistical background digging through such things, I have to give equal time to the flip side: having many different competent observers taking a crack at these numbers would, in fact, be a good thing.

Here's one effort of that sort, as detailed in Molecular Systems Biology. The authors have set up a database of all the side-effect information released through package inserts of approved drugs, which was much more of a pain than it sounds like, since the format of this information isn't standardized.

Looking over their data, the drugs with the highest number of side effects are the central nervous system agents, which makes sense. Many of these are polypharmacological; I'm almost surprised they aren't even worse by a wider margin. Antiparasitics have the fewest side effects (possibly because some of these don't even have to be absorbed?), followed by "systemic hormonal preparations". To be fair, the CNS category has the largest number of drugs in it, and those other two have the least, so this may be just a sampling problem. At a glance, one category that seems to have a disproportionate number of side effects, compared its number of approved drugs, is the "genitourinary/sex hormone" class, with muskoskeletal agents also making a stronger showing than their numbers might indicate.

Comments (15) + TrackBacks (0) | Category: Clinical Trials | Toxicology

Honesty, Of A Sort

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Posted by Derek

Chris Viehbacher, CEO of Sanofi-Aventis, gave a speech out at the recent J. P. Morgan healthcare fiesta in San Francisco. He spoke about how nasty the last ten years have been for the industry, calling it a "lost decade", but one particular item really caught my eye (emphasis mine):

". . .for the most part people have zero expectations of Sanofi-Aventis research and development,” he said. “We’ve basically cleared out a lot of bad news, and if anything comes along it should be good news.”

Well, that's one way to do it. I wonder if the performance reviews and yearly goal-setting forms over there read the same way?

Comments (17) + TrackBacks (0) | Category: Business and Markets

January 19, 2010

What Should Non-Chemists Know About Medicinal Chemistry, Anyway?

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Posted by Derek

It's been a busy day on the front lines of science around here; apologies for not getting anything up until now. Here's a topic that I was discussing with some colleagues not too long ago: how much do we need to know about each other's specialties, anyway? I'm assuming that the answer is "more than nothing", although if someone wants to make the zilch case, I'd be interested in hearing it done.

But once past that, what's the optimum? I (for example) have never done cell culture. Nor do I see myself ever needing to do it (and anyone who needs me to is clearly in a bad way). I know the broad outlines of the field, but almost none of the details, and I'm sure that even my broad outlines have some faint parts in them. So if I'm at some sort of meeting where the problem-of-the-day turns on cell culture issues, I can be of no help at all. Is this a problem? I understand that different cells take to culture conditions differently, have varying growth rates, need media changes and whatnot, can generally only be passaged a certain number of times, etc. In short, I know roughly what to expect from my cell culture colleagues, and what would be silly of me to demand. Is that about right?

After all, I don't expect them to know the ins and outs of medicinal chemistry, particularly the synthetic organic lab part of it. Things like methylene chloride being rather more weirdly polar as a solvent than you'd expect, or the fact that some amines will stick to solid magnesium sulfate drying agent (but not sodium sulfate), or how you can azeotrope out acetic acid with toluene, or how you want palladium tetrakis to be lemon yellow and not orange - these and dozens of others are the tricks of my lab trade, and they don't know mine in the same way that I don't know theirs.

But I do like it when my biology colleagues have the broad outlines - that molecules with chiral centers, other things being equal, are often harder to make than achiral structures, that sticking a lot of cycloalkyl grease on a molecule is asking for metabolic trouble (no matter what it does for the potency in the assays), what sorts of things tend to make a molecule more (or less) soluble, and so on. Those are the equivalent of me knowing that primary cell lines lose some of their functions in culture, the difference between transient transfection and a stable cell line, etc.

It seems to me that each discipline in our business could draw up a list of What Everyone Else In the Company Should Know about their area. So, to start off with, I'm throwing the comments section over to what biologists (and others) should know, at a minimum, about med-chem. Take it away!

Comments (54) + TrackBacks (0) | Category: Life in the Drug Labs

January 18, 2010

Oxford's New Building, One Year Later

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Posted by Derek

About a year ago, I wrote here about the impressive-looking new biochemistry building at Oxford, and wondered if it would work out quite the way the architects intended. Now I see a report from a post-doc who actually works there:

My first thoughts setting foot into the new building were the following: How are we supposed to concentrate with our offices in the atrium? How are we going to manage to work at such tiny desks?
I have to say, these initial concerns were justified. We hear the lab phone of every single floor ringing through the atrium, including people's mobile phones (which also causes envy towards those who actually have reception). When people really need to concentrate on writing, reading or thinking while others are discussing their work or are simply chatting, the atmosphere can get pretty tense. And even if it was completely silent in the atrium, the small size of the desks already makes working difficult. . .I once discussed the lack of space with our head of department. He simply replied: when you have to write a paper, you work from home anyway... I'd say £47 million well spent!

Anyone else over there want to comment?

Comments (48) + TrackBacks (0) | Category: Life in the Drug Labs

Correlations, Lovely Correlations

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Posted by Derek

Anyone looking over large data sets from human studies needs to be constantly on guard. Sinkholes are everywhere, many of them looking (at first glance) like perfectly solid ground on which to build some conclusions. This, to be honest, is one of the real problems with full release of clinical trial data sets: if you're not really up on your statistics, you can convince yourself of some pretty strange stuff.

Even people who are supposed to know what they're doing can bungle things. For instance, you may well have noticed a lot of papers coming out in the last few years correlating neuroimaging studies (such as fMRI) with human behaviors and personality traits. Neuroimaging is a wonderfully wide-open, complex, and important field, and I don't blame people for a minute for pushing it as far as it can go. But just how far is that?

A recent paper (PDF) suggests that the conclusions have run well ahead of the numbers. Recent papers have been reporting impressive correlations between the activation of particular brain regions and associated behaviors and traits. But when you look at the reproducibility of the behavioral measurements themselves, the correlation is 0.8 at best. And the reproducibility of the blood-oxygen fMRI measurements is about 0.7. The highest possible correlation you could expect from those two is the square root of their product, or 0.74. Problem is. . .a number of papers, including ones that get the big press, show correlations much higher than that. Which is impossible.

The Neurocritic blog has more details on this. What seems to have happened is that many researchers found signals in their patients that correlated with the behavior that they were studying, and then used that same set of data to compute the correlations between the subjects. I find, by watching people go by the in the street, that I can pick out a set of people who wear bright red jackets and have ugly haircuts. Herding them together and rating them on the redness of their attire and the heinousness of their hair, I find a notably strong correlation! Clearly, there is an underlying fashion deficiency that leads to both behaviors. Or people had their hair in their eyes when they bought their clothes. Further studies are indicated.

No, you can't do it like that. A selection error of that sort could let you relate anything to anything. The authors of the paper (Edward Vul and Nancy Kanwisher of MIT) have done the field a great favor by pointing this out. You can read how the field is taking the advice here.

Comments (13) + TrackBacks (0) | Category: Biological News | Clinical Trials | The Central Nervous System

January 15, 2010

Physics, for Dogs and Others

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Posted by Derek

Allow me to recommend a book I received a copy of recently, Chad Orzel's How to Teach Physics to Your Dog. Chad's a fellow scientific blogger from way back, and I have had a chance to consume chicken wings and trade lab stories with him. His new book is a fine addition to the what-the-heck-is-quantum-mechanics field, with some very good analogies and explanations. The format is conversational (which has a long history in the teaching of science), but this time, Orzel's dog is holding up the other end of the dialog. It's a device that lets him get at some pretty complex subjects - complex even for humans, I mean. (The famous Gary Larson "Far Side" cartoon, about dogs being so cute when they try to comprehend quantum mechanics does come to mind). Definitely worth a look.

Comments (12) + TrackBacks (0) | Category: Blog Housekeeping | Book Recommendations

Sirtuin Scenarios

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Posted by Derek

So, after reading what Pfizer has to say about Sirtris (and by extension, about GlaxoSmithKline's heavy investment in them), let's go over the possibilities. What happened, and what's going on?

We'll start out with the first branch point: either Pfizer (and Amgen) are right that there's trouble with the Sirtris assays and compounds (Reality A, I'll call it), or they're wrong (Reality B). For the rest of this piece, I'm going to assume that they're right, because I think that this is almost certainly the case. At least two separate groups of competent investigators have reported trouble, and that's good enough for me. (We'll discuss the implications of that in a bit).

Now we come to the second branch point: either Glaxo did enough due diligence to be aware of the problems (scenario A1) or they didn't realize them at the time of the deal (scenario A2). If A1 is the case, then we'd have to assume that the most likely consequence (A1a) is that Sirtris had other non-public assets that did check out, and that GSK's management felt that these justified the purchase. (A1b would be the scenario where GSK was well aware of the Sirtris problems, knew also that they didn't have anything else to offer, and bought them anyway, which doesn't make sense). These assets could have been other compounds, and/or a leg up on the complicated biology of this field. The difficulty with that line of thinking is that having found the fundamental assay problems with the Sirtris work, the GSK people would surely have been much more cautious about drawing sweeping conclusions about the rest of the company's intellectual property.

If A2 is the case, then we're looking at sheer fecklessness on the part of GSK's upper management. I'd like to be able to rule this out, but there have been other deals in the history of this industry that make that hard to do. I have witnessed at least one such personally. One problem is that these deals tend to be initiated near the highest levels of a company, and these people are not always the most technically savvy (or up-to-date) members of an organization. Even with a science background, the CEO of a large company does not have the time to be a scientist. (I'm reminded of Peter O'Toole's character in My Favorite Year: "I'm not an actor - I'm a movie star!"

Overall, though, I find it hard to believe that no one would have noticed the reported problems at all, which leads me to favor what I'll call scenario A3: the problems with the Sirtris assays may well have been known/realized at the lower scientific levels of GSK's organization, but these concerns may not have made it to the top in a sufficiently timely or vigorous manner. The deal would have gone through under its own momentum, then, in a flurry of last-minute misgivings which would have been hard to distinguish from the usual butterflies that accompany any large transaction or the preliminary stirrings of buyer's remorse. The sorts of reasons advanced in the A1 paragraph above would have been used to justify pushing ahead. With that in mind, this scenario could be broken down further into A3a, where Sirtris also had some other assets that the rest of us haven't seen, and A3b, where they didn't. I think that A3a is more likely, since that would have provided some of the momentum to get the deal done regardless. A3b is basically A2 with different timing and slightly less cluelessness.

So where do things go from here? That obviously depends on which of those three realities obtains. If A1 (specifically A1a) is the case, then GSK plows ahead with their secret Sirtris assets and compounds, and good luck to all concerned. It's worth keeping in mind that sirtuins are quite interesting and important, and that it's an area worth investigating on its own merits. (Pfizer and Amgen, among others, must think so too; that's the only reason that they would have been trying to replicate the Sirtris work).

If A2 is the real story, well, I'm very sorry to hear it. A lot of people seem ready to believe this one, partly because of anger over the layoffs the company has been going through. The most likely consequence of A2 is that $720 million dollars disappears, never to yield anything that's of use to anyone, so I hope that this isn't what happened.

And if, as I think, A3 is what actually happened, then that sort of depends on whether we're looking at A3a or A3b. If the former, then Glaxo overpaid, but has a fighting chance to redeem itself. If the latter, then Glaxo not only overpaid, but (as with A2) is in danger of losing its whole investment as well. We'll all find out.

But we may not find out very quickly. GSK has (like many other companies) a tendency to be rather close-mouthed about the progress of some of its research. When I worked in the nuclear receptor field, we all were very interested in the fate of a particular Glaxo compound, the first selective PPAR-delta ligand to go into the clinic. The company had talked about some animal and preclinical data, but we knew that they were taking it into humans (after all, it was listed that way in their pipeline updates). But it stayed listed like that. . .and stayed. . .and stayed. . .until, as the months and years passed, it became obvious to even the most optimistic observer that the compound's development was (at the very least) extremely complicated, and (more likely) had actually quietly ceased a good while before, albeit with no change in its public status.

In this case, now that these doubts have come up, GSK has a real interest in pointing out any success it may have. If its sirtuin compounds go into the clinic and just sort of hang there, that will probably be an even worse sign than usual. And if no sirtuin compounds even go into the clinic at all, well, the question has answered itself. I hope that's not what happens.

Comments (61) + TrackBacks (0) | Category: Aging and Lifespan | Clinical Trials | Diabetes and Obesity | Drug Development

January 14, 2010

Department of Placebo Effects

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Posted by Derek

Or nocebo, in this case, since people were sure that they were being harmed. Residents of a Johannesburg suburb detailed their reactions to a new cell phone tower in the area: rashes, headaches, nausea, disrupted sleep, and more. Electromagnetic poison, for sure. (Clearly they haven't heard that they might be at less risk for Alzheimer's).

What they didn't know was that the tower had been switched off for six weeks before the hearing. Descriptions of symptoms disappearing when the beleagured locals managed to sleep somewhere else for a night, only to reoccur when they came back to their homes, are thus a bit hard to reconcile. . .

Comments (22) + TrackBacks (0) | Category: Snake Oil

Gaining and Losing and Discovering and Selling

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Posted by Derek

Obesity has been one of those therapeutic areas that drug companies can't quite stay away from. A glance at the potential patient ranks, expanding in every sense of the word, is enough to explain why. But as I've detailed here in the past, finding an effective obesity drug is not easy, for many good reasons.

One response has been that such a drug wouldn't have to work spectacularly well to be effective, since calories add up so alarmingly. The "one cookie a day" model of weight gain is often referenced. But just how useful is it? According to this paper in JAMA (PDF), not so much (emphasis added):


How much weight would an individual gain by eating an extra chocolate chip cookie every day for life? One approach to answering this question, frequently used in textbooks and scientific articles, is based on the assumption that a pound (454 g) of fat tissue has about 3500 kilocalories (kcal). Thus, a daily 60-kcal cookie would be expected to produce 0.2 kg (0.5 lb) weight gain in a month, 2.7 kg (6 lb) in a year, 27 kg (60 lb) in a decade, and many hundreds of pounds in a lifetime. This of course does not happen. . .

So what does happen? If a person takes in a steady excess of calories, they most certainly will gain weight. But some of those extra calories then go into maintaining (and carrying around) that new weight. The result is a slow climb up to a new equilibrium weight. The 60-calorie cookie example above would be expected to lead to about 6 lbs of total weight gain over a period of years. Most of that will be put on early, with an asymptotic rise to the final value.

Now, if you're trying to avoid gaining weight, this is probably good news. The effects of having some extra food now and then aren't quite as catastrophic as the usual calculations would make you think (although there is that faster-weight-gain-at-first effect, so you have to separate the short-term and long-term consequences a bit). For someone that's significantly overweight and wants to lose it, the implications are mixed. One way to look at it is that the maintenance costs of extra body mass are substantial, meaning that a person doesn't have to suddenly go on a 1400-calorie-a-day diet to see results. Another thing this paper tells us that significantly overweight people have gotten to that point only by having significant calorie imbalances. A cookie a day is not going to do it. A lot of people are taking in a lot more excess calories than that:

These calculations suggest that small changes in lifestyle would have a minor effect on obesity prevention. Walking an extra mile a day expends, roughly, an additional 60 kcal compared with resting—equal to the energy in a small cookie. Physiological considerations suggest that the apparent energy imbalance for much of the US population is 5- to 10- fold greater, far beyond the ability of most individuals to address on a personal level. . .

The authors go on to call from greater regulation of the food supply, greater public health efforts, and so on, but I have to say that I'm skeptical of the ability of these to do the trick (or, given my political leanings, of the amount of coercion that might be needed to make them really work). It's clear that many people would like to be less overweight than they are, but (revealed preference time), it's also clear that they have enjoyed running up their caloric imbalances even more. So while the authors may be right that significant weight loss may be beyond most people's ability to address on a personal level, it's hard for me to see any other level that's really going to work.

So what would help? Would an anti-obesity drug? On the one hand, a good one might alter the physiological underpinnings of weight gain (and weight loss) in such a way to help people escape the squirrel-cage aspects of dieting and rebound weight gain. But that's asking a lot, and I remain uncertain about whether a really good weight-loss drug is even possible. The other difficulty is that any such treatment still has to be coupled with all those things that patients don't want to hear about: less food, more exercise. The time course needed is also a hard sell, particularly when you consider all the scam ads that bombard everyone. It seems clear that any sustainable weight loss probably should take about as much time as the initial weight gain did, which is not what many people are wanting to hear, particularly when someone else is promising umpteen pounds a week of magic weight loss.

Then there's the commercial consideration: that a new approved obesity drug, regardless of whether it works very well in the real world or not, would nonetheless sell like crazy. And if it doesn't work quite as well as the rigorously controlled clinical trials indicated it would, well, you can always blame the patients themselves (and for that matter, in many cases you'd be right). It's enough to make me think that the whole therapeutic area is a moral hazard.

Comments (32) + TrackBacks (0) | Category: Diabetes and Obesity

January 13, 2010

Two Doses of Crazy

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Posted by Derek

I'd like to take the time this morning to deal with two conspiracy theorists, and I'll take them in order of increasing foil-hat thickness. First up is Joe Collier, an emeritus professor who writes a blog for the British Medical Journal. He notes the recent study that suggested that cell phone emissions could have a beneficial effect in rodent models of Alzheimer's. I didn't give that any play on this blog - too many other things going on, and I don't find any rodent models of Alzheimer's particularly trustworthy to start with. But the study also showed (apparently beneficial) effects on normal rodents, and is certainly worth following up on.

But Collier takes this result and runs with it:

So what happens next? Faced with the prospect, albeit remote, of losing a lucrative market, I predict that the industry will want to quash the electromagnetic treatment theory as soon as possible. To this end, I would expect that the industry propaganda machine will go into overdrive in an attempt to undermine the credibility and findings of Arendash, and to overwhelm the decision makers (ultimately the funders) so that the use of drugs is maintained. The power of industry as an information generator and distributor is unmatched, and industry will use all its persuasive skills. . .

And so on, and so on. The problem (well, one problem) with this line of reasoning is that it could also be extended to other new drugs for Alzheimer's. If the industry wanted to keep selling the existing Alzheimer's drugs at all cost, why would we go to the trouble of trying to develop better ones? We are, you know - I have no idea how much money has vanished down that particular pipe, but it sure has been a lot, and I've helped flush some of it through myself. But we're not the monolithic "drug industry" over here. We're a bunch of companies climbing all over each other trying to make money, take each others' market share, and get to the clinic faster than the other guys down the road. That's what keeps things moving - everyone who's done industrial drug discovery has read a new press release or seen a new patent filing and heard the footsteps coming up from behind.

So I have a counterprediction for Collier. The South Florida study will, in fact, be followed up on. It's interesting enough. And if there's something to it, someone will find a way to optimize the effect and make money off it. And the drug industry will not mobilize to squash it, either - honestly, we have enough to do trying to get our own stuff to work. I haven't seen a single statement from a drug company about this study so far myself, and if Joe Collier has, I'd invite him to produce it.

Next! OK, now we move on to something that seems to be getting some more headlines in the past week or two, and that people have been e-mailing me about. One Wolfgang Wodarg, a German doctor and SPD politician, has been telling everyone that the handling of the H1N1 flu epidemic should be investigated because, he says, it's all a "fake pandemic" whipped up by the drug companies. (You can get all the Wodarg you need, and more, at his web site). Stories in the more excitable press make him sound like the head of all the health agencies of Europe, but people are confusing the Council of Europe (where Wodarg heads a subcommittee) with the EU, among other things they're mixing up.

The World Health Organization is now fielding questions about whether they oversold the epidemic, but it's a sure bet that (if it taken off more drastically) they'd be fielding even more about why they weren't prepared for it. At any rate, if you think that the Monolithic Drug Industry can simultaneously push around the WHO, the CDC, and the public health agencies of every other country in the world, I invite you to think again. If we could do all that, we'd at least be in good enough financial shape that we wouldn't be laying thousands of people off and doing ridiculous mergers out of desperation.

Wodarg, for his part, seems to have been sounding all kinds of alarms for a long time now. Back in the fall, he was telling everyone that the vaccine was going to give them cancer, for example. In case anyone's wondering, I treat his suggestions with the contempt that they appear to richly deserve.

Comments (34) + TrackBacks (0) | Category: Alzheimer's Disease | Infectious Diseases | Snake Oil | Why Everyone Loves Us

January 12, 2010

The Sirtris Compounds: Worthless? Really?

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Posted by Derek

As followers of the drug industry know, GlaxoSmithKline famously paid $720 million to buy Sirtris Pharmaceuticals in 2008. Sirtris is the most high-profile shop working on sirtuins and resveratrol-like pharmacology, which subject has received a massive amount of press (some accurate, some scrambled). I've been following the story with interest, since the literature has me convinced that the aging process can indeed be modified in a number of model organisms, which makes me think that it could be in humans as well. And I also feel sure that advances in this area could lead to many profound medical, social, and economic effects. (GSK, though, is going after diabetes first with the Sirtris deal, I should add - among other reasons, the FDA has no regulatory framework whatsoever for an antigeronic, if I can coin a word.)

But whatever the state of the anti-aging field, doubts have crept in about the wisdom of the Sirtris purchase. Last fall, a group at Amgen published a study suggesting that some of the SIRT1/resveratrol connections might be due an an experimental artifact caused by a particular fluorescent peptide. Now a group at Pfizer has piled on in the Journal of Biological Chemistry. They're looking over resveratrol and a series of sirtuin activators described by the Sirtris group in Nature.

And unfortunately, they also find trouble due to fluorogenic peptides. The TAMRA fluorophore on their peptide substrates seems to pervert the assay. While the Sirtris compounds looked like activators initially, switching to the native peptide substrates showed them to be worthless. Further study (calorimetry) showed that the activator compounds bind to a complex of SIRT1 and the fluorescent peptide substrate, but not to SIRT1 itself (or in the presence of native substrate without the fluorogenic group). That's not good.

But worse is to come:

"Despite a lack of evidence for the Sirtris series of compounds as direct SIRT1 activators, we investigated whether the in vivo efficacy demonstrated by SRT1720 in several rodent models diabetes could be validated and attributed to indirect activation of SIRT1. We therefore attempted to reproduce the in vivo efficacy for SRT1720 in mouse models of type 2 diabetes previously shown. . ."

That word "attempted" should tell you what comes next. The reported high dose of the compound (100 mpk) resulted in weight effects and death. The reported low dose (30 mpk) showed no effects at all on any diabetic parameters, but instead seemed to lead to increased feeding and weight gain. To complete the debacle, the Pfizer group screened the Sirtris compounds through a broad panel of assays, and found that all of them hit a number of other targets (and appear significantly worse than resvertarol itself, which is no one's idea of a clean compound to start with).

Basically, these folks have thrown down the gauntlet: they claim that the reported Sirtris compounds do not do what they are claimed to do, neither in vitro nor in vivo, and are worthless as model compounds for anything in this area of study. So what is GSK going to have to say about this? And what, if this paper is at all accurate, did they buy with their $720 million?

Comments (125) + TrackBacks (0) | Category: Aging and Lifespan | Business and Markets | Drug Assays

January 11, 2010

Sure About That?

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Posted by Derek

There was a natural products paper (abstract) that I missed last fall which has finally come out in Bioorganic and Medicinal Chemistry Letters. Let's have a show of hands: how many chemists out there think that this structure is the correct one?
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Right. Going back through SciFinder, I don't find any anti-Bredt cyclobutene structures of this sort in the modern era - only speculations about whether or not they could even exist. I hope, for their sake, that the authors have assigned this one correctly, and it certainly would be neat and interesting if they have. But doubts afflict me.

Note - the most recent entry on the (inactive?) med-chem blog "One in Ten Thousand" was a raised eyebrow about this exact paper. Fear not, there's no curse - I'll continue posting. . .

Comments (48) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News

MAGL: A New Cancer Target

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Posted by Derek

I do enjoy some good chemical biology, and the latest Cell has another good example from the Cravatt group at Scripps (working with a team at Brigham and Women's Hospital over here on this coast). What they've done is profile various types of tumor cells using an activity-based probe to search for changes in serine hydrolase enzymes. Those are a large and diverse class (with quite a few known drug targets in them already), and there had already been reports that activity in this area was altered as cancer cell lines became more aggressive.

What they tracked down was an enzyme called MAGL (monoacylglyceride lipase). That's an interesting finding. Cancer cells have long been known to have different ideas about lipid handling, and several enzymes in that metabolic area have been proposed over the years as drug targets. (The first one I can think of is fatty acid synthase (FAS), whose elevated presence has been correlated with poor outcome in several tumor types). In general, aggressive tumor cells seem to run with higher levels of free fatty acids, for reasons that aren't quite clear. Some of the downstream products are signaling molecule, and some of these lipids may just be needed for elevated levels of cell membrane synthesis.

But it looks from this paper as if MAGL could be the real lipid-handling target that oncology people have been looking for, though. The teams inhibited the enzyme with a known small molecule (well, relatively small), and also via RNA knockdown, and in both cases they were able to disrupt growth of tumor cell lines. The fiercer the cells, the more they were affected, which tracked with the MAGL activity they had initially. On the other hand, inducing higher expression of MAGL in relatively tame tumor cells turned them aggressive and hardy. They have a number of lines of evidence in this paper, and they all point the same way.

One of those might be important for other reasons. The teams took the cell lines with impaired MAGL activity, and wondered if this could be rescued by providing them with the expected products that the enzyme would deliver. Stearic and palmitic acid are two of the fatty acids whose levels seem to be heavily regulated by MAGL, and sure enough, providing the MAGL-deficient cells with these restored their growth and mobility. As the paper points out specifically, this could have implications for a relationship between obesity and tumorigenesis. (I'd add a recommendation to look with suspicion at other conditions that lead to higher-than-usual levels of circulating free fatty acids, such as type II diabetes, or even fasting).

It may be that I particularly enjoyed this paper because I have a lipase-inhibiting past. As anyone who's run my name through SciFinder or Google Scholar has noticed, I helped lead a team some years ago that developed a series of inhibitors for hormone-sensitive lipase, a potential diabetes target. We were scuppered, though, by the fact that this enzyme does (at least) two different things in two totally different kinds of tissue. Out in fat and muscle, it helps hydrolyze glycerides (in fact, it's right in the same metabolic line as MAGL), and that's the activity we were targeting. But in steroidogenic tissues, it's known as neutral cholesteryl ester hydrolase, and it breaks those down to provide cholesterol for steroid biosynthesis. Unfortunately, when you inhibit HSL, you also do nasty things to the adrenals and a few other tissues. There's no market for a drug that gives you Addison's disease, I can tell you.

So I wondered when I saw this paper if MAGL has a dual life as well. If I'd ever worked in analgesia or cannabinoid receptor pharmacology, though, I'd have already known the answer. MAGL also regulates the levels of several compounds that signal through the endocannabinoid pathway, and has been looked at as a target in those areas. None of this seems to have an affect on the oncology side of things, though - this latest paper also looked at CB receptor effects on their cell lines that were deficient in MAGL, and found no connection there.

So, what we have from this paper is a very interesting cancer target (whose crystal structure was recently reported, to boot), a new appreciation of lipid handling in tumors, and a possible rationale for the connections seen between lipid levels and cancer in general. Not bad!

Special bonus: thanks to Cell's video abstracts, you can hear Ben Cravatt and his co-worker Dan Nomura explain their paper on YouTube. The journal has recently enhanced the way their papers are presented online, actually, and I plan to do a whole separate blog entry on that (and on video abstracts and the like).

Comments (9) + TrackBacks (0) | Category: Biological News | Cancer | Diabetes and Obesity

January 8, 2010

Find That Pattern

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Posted by Derek

I have to take my hat off to this guy at the Times of London. The British press recently played a story about how various ancient sites were linked up in uncanny triangular formations - well, it turns out that the same chilling patterns are found in other ancient monuments as well. Read and be enlightened.

Comments (13) + TrackBacks (0) | Category: General Scientific News

Reasons Not to Go to Grad School?

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Posted by Derek

There's an article in the Chronicle of Higher Education that's been getting a lot of recent attention. It's titled "Grad School in the Humanities: Just Don't Go". The author, clearly (and to my mind, justifiably) embittered about what he sees happening, is an associate professor of English who sees no need to produce a huge surplus of people who want to go on to become associate professors of English.

Some of his warnings don't apply to the sciences. The biggest difference is that there have always been many more places to find work with a science degree other than academia, which is not so true if you've concentrated your graduate studies on the life of Rainer Maria Rilke. Another key factor is that we don't generally come out of grad school with academic debts. To be sure, a Rilke scholar would learn an awful lot about sponging money off wealthy people, but there's that pesky poetic talent problem to be dealt with before you can put those techniques into practice. . .

Of course, these days the jobs aren't exactly coming so readily for new science graduates, although we're still in better shape than anyone over in the humanities. A lot of people are rethinking grad school, though, if the mail I get is any indication. For what it's worth, I offer the Chronicle author's list of bad reasons why people take on graduate study in the humanities - let's take a look and see how many apply to the sciences. I'm going to number them for easy reference:

(1) They are excited by some subject and believe they have a deep, sustainable interest in it. (But ask follow-up questions and you find that it is only deep in relation to their undergraduate peers — not in relation to the kind of serious dedication you need in graduate programs.)
(2) They received high grades and a lot of praise from their professors, and they are not finding similar encouragement outside of an academic environment. They want to return to a context in which they feel validated.
(3) They are emerging from 16 years of institutional living: a clear, step-by-step process of advancement toward a goal, with measured outcomes, constant reinforcement and support, and clearly defined hierarchies. The world outside school seems so unstructured, ambiguous, difficult to navigate, and frightening.
(4) With the prospect of an unappealing, entry-level job on the horizon, life in college becomes increasingly idealized. They think graduate school will continue that romantic experience and enable them to stay in college forever as teacher-scholars.
(5) They can't find a position anywhere that uses the skills on which they most prided themselves in college. They are forced to learn about new things that don't interest them nearly as much. No one is impressed by their knowledge of Jane Austen. There are no mentors to guide and protect them, and they turn to former teachers for help.
(6) They think that graduate school is a good place to hide from the recession. They'll spend a few years studying literature, preferably on a fellowship, and then, if academe doesn't seem appealing or open to them, they will simply look for a job when the market has improved. And, you know, all those baby boomers have to retire someday, and when that happens, there will be jobs available in academe.

Reason #1 is probably common, to some degree, across all academic fields. Graduate school is, in fact, largely about finding out whether you have enough dedication to get through graduate school (and is used as a credentialing signal for that very reason). Reason #2 also probably happens to some extent everywhere, but in science research programs there often aren't any grades after the first year. You have to get your validation from getting good ideas and getting your research to work, with is the same situation that obtains in the real world of science.

Reasons #3 and #4 are actually some of the things that keep people in grad school too long. Though the environment can be odd and stressful, you come to feel at home in it, and worry about going to some new situation where you won't have a place that you've made for yourself. Everyone in the sciences has known people in grad school who've stalled out for just these reasons.

Reason #5 doesn't apply as much for the sciences, I'd say. The kinds of jobs available to someone with just an undergraduate degree are often much different than the ones open to people with graduate training. And the material that you learn in grad school is much like what you started to learn as an undergraduate, just more of it and in more detail. The biggest change is in actually applying it to real research, instead of just learning it and doing well on a written test about it. That's another transition that throws some people out of a scientific career.

But reason #6 would definitely seem to apply, both for academic and industrial jobs. I'd have to think that we have a lot of people who are taking a bit longer to finish their PhDs than they might have otherwise, and a lot of people looking for post-docs who might otherwise not have done one, while they wait for the job market to improve. . .

Comments (42) + TrackBacks (0) | Category: Academia (vs. Industry) | Graduate School

Carl Icahn Going For Genzyme?

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Posted by Derek

That's what the folks at Fierce Biotech are saying. No doubt he sees an opening, given the company's current manufacturing troubles, and is planning to give them the same treatment he's been giving Biogen, just down the road. There are quite a few glossy condominium units available in Cambridge these days; maybe Icahn should buy one as a pied-a-terre if he's going to keep this stuff up.

But I hope that he doesn't. While I agree that it's worth having some corporate raiders around to keep companies on their toes, I think the nature of the biotech industry keeps things lively enough already. I tend to agree with Schumpeter's ideas about "creative destruction", but I worry that Icahn slips too often over to the "noncreative but lucrative" end of the destruction scale.

Comments (2) + TrackBacks (0) | Category: Business and Markets

January 7, 2010

Is XMRV the Cause of Chronic Fatigue Syndrome? Or Anything?

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Posted by Derek

Last fall it was reported that a large proportion of patients suffering from chronic fatigue syndrome also showed positive for a little-understood retrovirus (XMRV). This created a lot of understandable excitement for sufferers of a conditions that (although often ill-defined) seems to have some puzzling biology buried in it somewhere.

Well, let the fighting begin: a new paper in PLoS One has challenged this correlation. Groups from Imperial College and King's College have failed to detect any XMRV in a similar patient population:

. . .Unlike the study of Lombardi et al., we have failed to detect XMRV or closely related MRV proviral DNA sequences in any sample from CFS cases. . .Based on our molecular data, we do not share the conviction that XMRV may be a contributory factor in the pathogenesis of CFS, at least in the U.K.

Interestingly, XMRV has also been reported in tissue from prostate cancer patients, but recent studies in Germany and Ireland failed to replicate these results. Could we be looking at a geographic coincidence, a retroviral infection that's found in North America but not in Europe, and one whose connection with these diseases is either complex or nonexistent?

Note: as per a comment on this post, the Whittemore Peterson Institute is firing back, claiming that their original work is valid and that the London study has many significant differences. PDF of their release here.

Comments (94) + TrackBacks (0) | Category: Biological News | Cancer | Infectious Diseases

Extortion, Retractions, And More

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Posted by Derek

Now here's a strange tale, courtesy of Science magazine, about some retracted work from Peter Schultz's group at Scripps. Two papers from 2004 detailed how to incorporate glycoslylated amino acids (glucosamine-serine and galactosamine-threonine) directly into proteins. These featured a lot of work from postdoc Zhiwen Zhang (who later was hired by the University of Texas for a faculty position).

But another postdoc was later having trouble reproducing the work, and in 2006 he made his case for why he thought it was incorrect. Following that:

Schultz says the concerns raised were serious enough that he asked a group of lab members to try to replicate the work in Zhang's Science paper in addition to several other important discoveries Zhang had made. That task, however, was complicated by the fact that Zhang's lab notebooks, describing his experiments in detail, were missing. Schultz says that in the early fall of 2006, the notebooks were in Schultz's office. But at some point after that they were taken without his knowledge and have never resurfaced.

After considerable effort, Schultz says his students were able to replicate most of the work. The biggest exception was the work that served as the basis for the 2004 Science and JACS papers. "It was clear the glycosylated amino acid work could not be reproduced as reported. So we tried to figure out what was going on," Schultz says.

So far, so not-so-good. But here's where things get odd. Around this time (early 2007), Zhang started to get e-mails at Texas saying that unless he send $4000 to an address in San Diego, the writer would expose his "fraud" and cause him to get fired. The messages were signed "Michael Pemulis" - Science doesn't pick up on that pen name, but fans of the late David Foster Wallace will recognize the name of the revengeful practical joker from Infinite Jest.

That brings up another point: the e-mails quoted in the Science article are in somewhat broken English: "you lose job. ... Texas will fire you before you tenure. . ." and that sort of thing. But my belief is that no one who drops the second person possessive while writing would make it far enough into Infinite Jest to meet Micheal Pemulis and use him as an appropriate alias for an extortion plot.

At any rate, after the San Diego police got involved, they told Zhang that they had a suspect, but Zhang decided not to press charges. That fall, though, "Pemulis" dropped the bomb, with a hostile anonymous letter to everyone involved - officials at Scripps and UT-Austin, the editors at Science, etc. In 2009, Zhang was denied tenure. The postdoc mentioned above (now at Cardiff) has published a paper in JBC detailing the problems with the original work. (He denies having anything to do with the missing lab notebooks or the threats made to Zhang). And everyone involved is still wondering just what is going on. . .

I certainly have no idea. But I can say this: although I've spent a lot more time in industry than in academia, a disproportionate number of the people I've worked with over the years that I consider to have had serious mental problems are still from my academic years. Whoever "Pemulis" is, I'd put him or her into that category. Grad students and post-docs are under a lot of pressure, and some of them are at a point in their lives when their internal problems are starting to seriously affect them.

Comments (49) + TrackBacks (0) | Category: Biological News | The Dark Side | The Scientific Literature

January 6, 2010

Five Technologies For the Scrap Heap?

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Posted by Derek

Xconomy has a piece on biotechnologies that look to be headed for obsolescence. I think the list is mostly correct - it includes the raw proteomic approach to understanding disease states and a lot of the biomarker work being done currently. I won't spoil the rest of the list; take a look and see what you think. Note: RNA interference is not on it, in case you're wondering. Nor are stem cells.

Comments (10) + TrackBacks (0) | Category: Biological News

Lilly's R&D Outsourcing

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Posted by Derek

Yesterday's Wall Street Journal ran a story on Eli Lilly, all about how the company is outsourcing a lot of their drug development work. Since Lilly signed a big deal with Covance in 2008 to do just that sort of thing, the first thing you have to wonder is "Is this news?"

But some of the spin in this piece is interesting. Here, see what you think:

Not long ago, a big pharmaceutical company wouldn't have considered farming out the development of a compound found in-house. But expiring patents on top-selling drugs and high-profile failures in finding their replacements have pushed the biggest drug makers to "externalize" much of their R&D, said Peter Tollman, who advises drug makers at Boston Consulting Group. . .

. . .Lilly is relying on outside firms called contract research organizations to do the work. Company researchers, Mr. Tollman said, can get too attached to their own compounds to know when to let them go.

I'm not buying that last part at all. To me, the main reason that Lilly has been using CROs so much (through an R&D unit named Chorus) is that they feel that they can do the job more cheaply. The next most important reasons after that one are (1) that they can do the job for less money, (2) that they can do the job without Lilly spending so much cash, and (3) that they can do the job at lower cost. Have I left anything out?

As a correspondent put it, once you get into the clinic, "the data are the data", whether you're attached to the compound or not. The bigger danger is in how you set up the trials in the first place, whether you've done them in a realistic fashion, and a CRO can fall victim to that just as much as anyone else can. The same incentives are there to fool yourself. So I don't see any special magic in outsourcing clinical work, other than the fact that CROs tend to work their people harder and pay them less money.

To be fair, the rest of the article does show the flip side:

Skeptics say such results may cut R&D costs, but don't address big pharma's main problem of finding new therapies that pan out.

"You get more negative results faster and cheaper," said James Niedel, a former GlaxoSmithKline executive who is now a partner at New Leaf Venture Partners fund. "But the problem with the industry is they're not getting enough positive results and that depends on knowledge and insight about biology and disease" that might be lacking among CROs. . ."Neither the cost cuts nor the structural changes help R&D productivity," said Keyur Parekh, a UBS analyst who thinks Lilly might need to make acquisitions to replenish its pipeline.

Indeed. It's important not to spend money where you don't have to, but it's also important to have things to spend the money on in the first place.

Comments (31) + TrackBacks (0) | Category: Clinical Trials | Press Coverage

January 5, 2010

Always Read the Fine Print

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Posted by Derek

. . .especially when you're dealing with the Swiss. You'll have probably seen that Novartis is buying Alcon. But what price they're buying them at depends on who you are.

As the Wall Street Journal reports, Novartis, who already had 25% of Alcon's stock, is paying majority shareholder Nestlé $180/share for their 52% stake in the company. Minority shareholders - that is, all the rest of them - are being offered $153. Some of these folks have paid up over $160/share recently, anticipating such a deal, but under Swiss law, there's not a thing that they can do about it. . .

Comments (6) + TrackBacks (0) | Category: Business and Markets

Run It Past the Chemists

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Posted by Derek

I missed this paper when it came out back in October: "Reactome Array: Forging a Link Between Metabolome and Genome". I'd like to imagine that it was the ome-heavy title itself that drove me away, but I have to admit that I would have looked it over had I noticed it.

And I probably should have, because the paper has been under steady fire since it came out. It describes a method to metabolically profile a variety of cells though the use of a novel nanoparticle assay. The authors claim to have immobilized 1675 different biomolecules (representing common metabolites and intermediates) in such a way that enzymes recognizing any of them will set off a fluorescent dye signal. It's an ingenious and tricky method - in fact, so tricky that doubts set in quickly about the feasibility of doing it on 1675 widely varying molecular species.
Reactome%20slide.jpg
And the chemistry shown in the paper's main scheme looks wonky, too, which is what I wish I'd noticed. Take a look - does it make sense to describe a positively charged nitrogen as a "weakly amine region", whatever that is? Have you ever seen a quaternary aminal quite like that one before? Does that cleavage look as if it would work? What happens to the indane component, anyway? Says the Science magazine blog:

In private chats and online postings, chemists began expressing skepticism about the reactome array as soon as the article describing it was published, noting several significant errors in the initial figure depicting its creation. Some also questioned how a relatively unknown group could have synthesized so many complex compounds. The dismay grew when supplementary online material providing further information on the synthesized compounds wasn’t available as soon as promised. “We failed to put it in on time. The data is quite voluminous,” says co-corresponding author Peter Golyshin of Bangor University in Wales, a microbiologist whose team provided bacterial samples analyzed by Ferrer’s lab.

Science is also coming under fire. “It was stunning no reviewer caught [the errors],” says Kiessling. Ferrer says the paper’s peer reviewers did not raise major questions about the chemical synthesis methods described; the journal’s executive editor, Monica Bradford, acknowledged that none of the paper’s primary reviewers was a synthetic organic chemist. “We do not have evidence of fraud or fabrication. We do have concerns about the inconsistencies and have asked the authors' institutions to try to sort all of this out by examining the original data and lab notes,” she says.

The magazine published an "expression of concern" before the Christmas break, saying that in response to questions the authors had provided synthetic details that "differ substantially" from the ones in the original manuscript. An investigation is underway, and I'll be very interested to see what comes of it.

Comments (46) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | Drug Assays | The Scientific Literature

January 4, 2010

Remember Apo-A1 Milano? Pfizer Does.

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Posted by Derek

The folks over at the In Vivo Blog will soon be announcing their "Deal of the Year" in the biotech/pharma sector (you can scroll back over there to see the various nominees). But they could just as well run the competition in reverse, and award some retroactive Bad Deal statues based on what's been happening recently.

One of those might well go to the 2003 deal in which Pfizer paid over a billion dollars in to acquire Esperion and their Apo-A1 Milano lipoprotein. If you've been following the cardiovascular field for a few years, you'll remember the big press that this got. The Milan variant of the protein seemed to be quite effective at reverse cholesterol transport - just typing that phrase takes me back a few years, to be honest. The hope was that periodic treatments might flush the arteries out and avert atherosclerosis.

And there things seemed to stay, hung up in that "promising therapy" zone. At the time, Pfizer was going to be the biggest thing ever in cardiovascular, what with Lipitor, with their CETP inhibitor torcetrapib, and with Apo-A1 Milano coming along at the same time. That dream is a pile of wreckage now, of course - Pfizer has de-emphasized the whole area. Esperion itself was spun back out in 2008 as a much smaller operation, minus the lipoprotein it came in with, and now Apo-A1 Milano itself has been sold off to The Medicines Company. For $10 million up front.

Yep, Pfizer gets $0.01 billion back from its $1.25 billion investment - well, more if things work out, but you'd have to think that most of that money is just gone. But I can't really say that this is just Pfizer's own problem, or just their own folly. This sort of thing can happen to any organization, and the larger it is, the more likely it is to make some sort of Big Move which then sends it falling down the stairs. After all, if you're trying to affect the future of a huge company, you have to do huge things, right? And these huge things take on a momentum of their own - witness another Pfizer disaster, Exubera. That inhaled insulin was going to be a billion-dollar drug, no question about it, and no one could tell the company any different. Well, except their customers.

But again, I don't see these things as coming from some particularly Pfizery mindset. Any other drug company of that size would probably have done things equally catastrophic, and as they get larger, the others surely will find their own open manholes to step confidently into. Since this is the first post of the new year, here's a resolution I wish the industry would consider: no big mergers in 2010. No gigantic sense-of-urgency do-this-deal-now productions, please. Let's try to do what we do better, rather than just do more of it.

Comments (24) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Industry History