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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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September 30, 2005

And Another Thing. . .

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Posted by Derek

I wanted to let people know that I have an opinion piece up at the Manhattan Institute's "Medical Progress Today" site, on the FDA's conflict of interest rules for their advisory panels. There are some proposed changes that I don't think will work out very well. . .

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

September 29, 2005

The Hazards of Molecular Modeling

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Posted by Derek

A comment to the last post really gave me the shivers:

"I like to think of modelling as the "silent killer". It is easy to rely on it for quick answers, and easy to forget that there is no substitute for an actual experiment. . .

I remember asking a fellow scientist if a particular molecule performed as hypothesized, the response was: " I don't know. It did not dock well into the enzyme, so I didn't make it."

I've made this point before, but it needs to be made again: molecular modeling is not reality. Most models are not that good, or only good around a limited group of rather similar compounds. If you as a medicinal chemist are crossing out easy-to-make compounds in unexplored chemical space just because the software doesn't like it, you are handcuffing yourself and tying your thumbs together. Stop it, stop it for your own good, or you may never discover anything unexpected or useful.

"The silent killer": I like that phrase a lot. I get the occasional testy e-mail from the computational types when I talk like this, but I'm sticking to my beliefs here. Molecular models based on numerous high-resolution X-ray structures are, I think, sort of useful, sometimes. Models based on only one X-ray structure are to be approached with great caution. And binding models that are just calculated up de novo should be treated as hazardous to your scientific health, unless you have a great deal of evidence to make you think otherwise.

OK, you silicon jockeys, go ahead and flood my in-box. I've earned it.

Comments (7) + TrackBacks (0) | Category: In Silico

September 28, 2005

Clamping Down, or Loosening Up?

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Posted by Derek

We medicinal chemists spend our days trying to make small molecules that bind to targets in living systems. Almost all of those targets are proteins of one sort or another, and most of them have binding pockets already built into them, which we're trying to hijack for our own purposes. Molecular modelers try to figure out how these things fit together, but there are still a lot of unknowns in what would seem so basic a process.

I'm willing to bet that most chemists and biologists have a mental picture of a small molecule ligand fitting into a binding site which involves the protein sort of folding down around things - gently biting down on the ligand, as it were. It seems intuitively obvious that a protein's motions would settle down once it complexes with its target molecule.

And like a lot of intuitively obvious things in drug research, that idea appears to be mistaken. There's a recent study in the Journal of Medicinal Chemistry from a group at Michigan that tackles this question in a rigorous manner. They looked through the X-ray crystal structure data banks for proteins that have had high-quality structures determined both with and without small molecules bound in them. After controlling for experimental conditions (the temperature that the X-ray structure was taken at, among other things) and for the way the data were processed, they still had a few dozen closely matched pairs.

What they found was that in most of these structures, at least some of the atoms in and near the binding site are more mobile when there's a ligand bound. At times, the effect was pretty dramatic, with the entire binding site becoming more flexible, weirdly enough. Examples where everything got less mobile were found, but that only happened in a minority of the cases. The proteins the authors studied were scattered across a wide range of structural and functional classes, and there's no reason to think that they hit on an anomalous data set.

So, we're going to have to adjust our mental pictures, and the molecular modelers will have to adjust their simulations. I'd like to know just how many of those in silico models of binding would have predicted this greater flexibility. I fear that the answer is "darn near none of them". We have a long way to go.

Comments (9) + TrackBacks (0) | Category: In Silico

September 27, 2005

Tribes

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Posted by Derek

There are some pretty big cultural divides in the drug industry. The preclinical research people and the development people always think that they have one of the biggest, but that's not true. They do argue a lot, but the arguments are phrased in terms that each side understands. "Your synthetic route can't provide enough compound" "You're testing at too high a multiple for a toxicity dose" - these are worthy points to disagree on. Someone's going to win, and someone's going to lose, and both parties will know it, and they'll know why. That's why the discussions are so intense.

Try the space between marketing and research - now there's a canyon for you. During the periodic attempts to get these two groups to work with each other, each one feels as if it's making First Contact with an alien race. Marketing is such an imprecise world compared with the physical sciences (which are so cut-and-dried compared to marketing, as far as they're concerned) that sometimes they just talk past each other.

But for real extraterrestrials (as far as the research folks are concerned), you just have to go to HR. Of course, they feel exactly the same about us. Part of that is because the scientific habit of asking "Hmmm. . .I wonder if that's true?" doesn't make many HR presentations go more smoothly. I'll admit that it's hard to get real data on how well most human resources initiatives and techniques actually work, but you wouldn't know that to talk to some of the more enthusiastic practitioners. What's interesting is how they're generally just as perky about the next managerial fad, which generally comes along every three to five years.

I'm certainly not saying that scientists would be any good at the HR jobs, although we'd probably be better at theirs than they would at ours. Still, putting us in charge of problems that can't be settled by collecting more data probably isn't a good idea. Then there's the personality problem. Even though the real crazies are found mostly in academia, plenty of industrial researchers have people skills that need some fine sandpaper work and a coat of rustproof primer. No, you don't want a bunch of chemists and biologists running that shop. . .but just who do you want running it?

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs

September 26, 2005

Antivirals "Gathering Dust"?

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Posted by Derek

The CBC has an article claiming that:

"Formulas for new, inexpensive influenza drugs that could expand the world's tiny arsenal of weapons against pandemic flu are gathering dust because the pharmaceutical industry isn't interested in developing them, scientists say.

They believe governments should fund the testing and development of the drugs, side-stepping big pharma and bringing them to market as cheap generic medications.

And they point to the story of Relenza - one of only four flu drugs currently sold - as evidence public-sector involvement will be needed if crucial new flu drugs are ever going to hit pharmacy shelves. . ."

Which scientists say these things? Well, one of them is Mark von Itzstein, of Griffith University in Australia, who is quoted as saying that he has "three compounds that are ready to be tested in animals and could be available on a commercial basis in three to five years for about $10 a treatment course". You have to get to the end of the article to get to some of the problems with that statement, and some of them never make it to the surface at all.

For one thing, having three compounds that are ready to be tested in animals is not as big a number as it might sound. I've been on projects where many more compounds than that - about ten times more, in some cases - went into animal testing, and nothing still came out the other end. It's good to have compounds that you believe in, but Prof. von Itzstein (who helped discover the drug now sold as Relenza) surely knows, you usually need a lot more shots on goal than that.

Another little detail is that going from this unspecified "animal testing" (efficacy model? two-week toxicity?) to "available on a commercial basis" in under five years is rather unlikely. That's a very, very short time for drug development, and I don't see how all the regulatory requirements could be met so quickly. And having a cost estimate in hand makes it seem as if there's already a bulk synthesis of the compounds, but why would you do that before you've even come close to going into animals?

This all has to do with a Worthwhile Candian Initiative called ICAV, which aims to get more antiviral drugs on the market. I certainly can support that idea, but I think that the people involved will soon find out one reason why there aren't more of them already: antiviral drug development is very hard. There are a lot of disparaging references in that CBC article about the profit-driven drug companies ignoring all these worthy drugs, but then there's this:

"ICAV is trying to get buy-in from governments around the world, starting with Canada. It has asked the federal government for $70 million over seven years to promote development of antiviral drugs for a number of diseases, including influenza, HIV and hepatitis C."

You know, I could have sworn that those indications could all support profitable drugs - if of course, they, like, work and everything. One of the problems with neuraminidase inhibitors like Relenza is that they have to be administered rather soon in the disease's progression, or they're basically useless. That's one reason that they haven't caught on, together with their often less-than-compelling efficacy. But getting antivirals with compelling efficacy is, as mentioned, hard. Those of us over in the profit-driven drug industry can only agree with Prof. von Itzstein wholeheartedly when he's quoted as saying "We need new antivirals." The only thing I would add is just a "good" in the middle of that sentence.

Comments (7) + TrackBacks (1) | Category: Infectious Diseases

September 25, 2005

Report From What I Think is the Frontier

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Posted by Derek

It's been a while since I spoke about the run of experiments that I've been doing. Things are going very well, although not quickly. The combination that seemed to work for me back in June (see the 6/23 post here) has repeated cleanly several times now, with new control experiments and fresh solutions of everything. And since then, I've found a couple of others that also seem to give the effect I'm after and they hold up, too. I'm having to make the mental adjustment of realizing that this stuff is real and reproducible.

I mentioned that I was going to present my results inside my company. That went fine, I think, with about the same number of people leaving the room thinking that I was nuts as came in. Mind you, there was some turnover in the rosters of people holding each opinion. But I've been given a bit of room to work on what's now generally known as Derek's Crazy Idea. I have a two-week experiment going on to get some kinetic data on things - how quickly does this stuff come on, how high can it go, when does it start to level off, and so on. And I'm getting geared up for an extension to a completely different system, one that's much less of a test bed and much more of a real-world application.

That makes me rather nervous, because there's plenty of twangy tightrope stretched between those two platforms. My preparations include gearing up for a huge range of reaction conditions, because what my work thus far has shown is that I don't have a clue - yet, anyway - about what's going to work and what isn't. When I think about how close I came in the first system to never seeing anything at all, it makes me want to sit down for a while. How many other interesting things have I missed in my research career, slipping past me by only a couple of millimeters and still leaving no trace?

Comments (5) + TrackBacks (0) | Category: Birth of an Idea

September 22, 2005

By a Nose in a Head to Head

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Posted by Derek

One of the other incorrect lessons that people might take away from the press accounts of the antipsychotic trial is that drug companies have been comparing their medications to placebo too often. And why would you do that unless you were scared that you wouldn't be better than the competition? What's with these people, anyway?

Well, there are fields where placebo-controlled trials take place, and fields where they don't. It depends on the disease and options available to treat it. Cancer trials, for example, are very rarely run against placebo, unless there's just nothing left to do. (You'll see this with drugs that are meant for late-stage patients or those who have failed existing therapies.)

Antipsychotics are generally compared to an existing standard of care, because it's unethical to leave someone untreated when they've already been diagnosed as schizophrenic. The problem that the CATIE trial uncovered, though, is that many trials are run against haloperidol (known as Haldol). That's a typical older drug, and companies have been showing that they have better efficacy and fewer side effects than it does. (It's known to have significant problems with tardive dyskinesia, among other things).

But now we know that perphenazine is a better standard among the older drugs, mostly because of fewer side effects. I don't think that anyone is going to be able to run a haloperidol-controlled trial for a new antipsychotic. Now you're going to have to beat perphenazine, which will be a higher standard. The newer drugs have been able to get rid of the so-called extrapyramidal side effects, like tardive dyskinesia, but they haven't been able to increase their efficacy that much. That's not going to be enough any more - the ante has gone up in the field of schizophrenia therapy.

Now, if you think that your new drug is really going to cream the competition, running a trial against them is a smart move. There's no better way to persuade people to prescribe your drug than to show that it's clearly better than what's out there now. Another time you see head-to-head trials is when a company is making a run at the leader in a given category. The various attempts to out-do Lipitor are good examples, not that any of them have succeeded. But there really wasn't a clear leader in the antipsychotic area, and thus no real target to try to knock down. I'd bet that the companies involved strongly suspected that their own drugs weren't head and shoulders above everything else, either. This is the perfect situation for an outside agency like the NIH to do a comparison study, because if you're waiting for the companies involved to do it, you're going to have a pretty long wait.

Comments (4) + TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | The Central Nervous System

September 21, 2005

No Clear Winners

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Posted by Derek

You've probably seen the headlines about the recent NIH-sponsored "CATIE" study comparing five anti-psychotic medications. The result, which is what made the whole thing newsworthy to the popular press, was that it was hard to distinguish among them, with the oldest generic working as well as (or better than) the newer drugs.

But I think that people outside of the medical world are going to learn the wrong lessons from all this. Does this study mean that everyone taking anti-schizophrenia medication should switch to the old generic? Not at all, although if they need to try a different medication, they should definitely consider it. Does it mean that all these newer drugs are unnecessary? No, again. There's an awful lot of patient-to-patient variation in central nervous system drugs. Says the study's principal investigator, Dr. Jeffrey Lieberman of Columbia:

"There is considerable variation in the therapeutic and side effects of antipsychotic medications. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication. What works for one person may not work for another."

But I think that this study does make clear that the newer antipsychotics aren't as good as they should be. The field is a tough one, as I know from personal experience, having played a small role in helping a company spend I've-no-idea-how-many millions of dollars to find out that a potential schizophrenia medication didn't do squat. There's a lot of room for improvement, and we haven't been able to improve things very much.

It's important to emphasize that this was a surprising result. No one expected the side effect profiles of the four "second-generation" drugs to be so similar to the older one (perphenazine), and so similar to each other. That's one reason that a study like this is so valuable - huge clinical trials that tell you something that you already knew aren't too wonderful. I think that this is an excellent thing for the NIH to be doing. Tomorrow: what this says about head-to-head trials in general.

Comments (4) + TrackBacks (0) | Category: "Me Too" Drugs | Clinical Trials | The Central Nervous System

September 20, 2005

Say It Again!

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Posted by Derek

From the editorial pages of the Washington Post we have this, and I could not have said it better myself:

. . .Unfortunately for Merck, scientific facts didn't play much of a role in the first Vioxx trial, which ended on Aug. 19. The Texas jury in that case awarded $253.4 million to the widow of a man who died of a heart attack triggered by arrhythmia, which is not a condition Vioxx has been proven to cause. The jury, declaring that it wished to "send a message" to Merck, decided to make an enormous symbolic award anyway. Besides, said one juror afterward, the medical evidence was confusing: "We didn't know what the heck they were talking about." Because Texas law limits the size of jury awards, the final cost to Merck is likely to be closer to $2 million. But the precedent set by the jury is ominous. Merck is facing about 5,000 similar lawsuits. If every one of those costs the company $2 million, the total price will come to $10 billion -- if, of course, a company called Merck is still around to pay it.

Politicians and regulators should be asking themselves whether a system of massive cash awards to people who may or may not have been adversely affected by Vioxx is a logical, fair or efficient way to run a drug regulatory system. They should also be asking whether juries that scorn medical evidence are the right judges of what information should or should not have been on a prescription label. After all, Vioxx was produced and sold legally. The drug was approved by the Food and Drug Administration, and its label did warn of coronary side effects. It is possible, even probable, that Merck was negligent in its decision to ignore early warnings of the cardiovascular risks of Vioxx. But the company has already paid a price for that negligence, in the losses it has suffered after abruptly taking Vioxx off the market. Fair compensation for the injured needn't entail disproportionate financial punishment as well. . .

That is exactly my opinion on the matter, and it is a weird experience, for me at least, to have my views line up so perfectly with those of a major newspaper's editorial page. If the New York Times had come out with this one, I'd have to sit down and fan myself for a while. Let us celebrate this gust of good sense and hope for more of the same, as the second Merck/Vioxx trial (in New Jersey, this time) goes hammering along. . .

(Link via Marginal Revolution.)

Comments (11) + TrackBacks (1) | Category: Press Coverage

September 19, 2005

Klotho: Sooner Than You Think?

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Posted by Derek

There's been a lot of news in the aging-research area about the Klotho gene (and its associated protein) the last few years. Now there's a recent paper in Science that is bringing it back into the spotlight.

I won't go into all the details - that link and this one will give you some good background - but the short form is that adding an extra Klotho gene extends mouse lifespan by up to 30%. (It was already known that deleting the gene shortened lifespan drastically - the paper we're seeing now is the result of an immediate effort to take the system in the opposite direction. Aging research takes a long time!)

Some of the most interesting anti-aging genes that have turned up in roundworms and flies have to do with insulin (and insulin-related growth factor, IGF) signaling. This team of researchers thought that the Klotho protein might fall into the same category, and they were right: the protein seems to lower insulin sensitivity by affecting signaling through the insulin and IGF receptors.

Here's where my drug-discovery radar started pinging. These receptors are part of a family that carries their own kinase along to phosphorylate themselves, and that's a key even in their signaling cascade. This new work noted that Klotho suppressed autophosphorylation of the receptors, and that makes sense, considering the downstream effects. It's very interesting to note that compounds that affect the IGF receptor kinase are already being developed. They're potential anticancer agents, and a number of companies seem to be working on them.

Now, I'm not aware of anything that's been developed to inhibit the insulin receptor kinase, mainly because no one has seen a market for giving people a sort of quick-acting type II diabetes. But it's certainly possible that such a compound could be discovered, if someone were to look. What would the effects be of lower doses of such kinase inhibitors in normal humans? Could one get the effect of the Klotho hormone through that route, or does it cause other things to happen through its own pathways?

I think someone's going to be tempted to find out. Intense work is doubtless in progress in this area, and there will be many more things to be discovered. But if the insulin/IGF story continues to hold up, I don't see what's going to stop people from trying this out on themselves or on others. It's probably the nearest thing in the whole field to being realized in practice. And if it doesn't happen here, it might take place somewhere else with more. . .relaxed clinical standards. Worth keeping an eye on. . .

UPDATE: ". . .I just wish I understood more than every third word." Well, that was a kind of condensed post, I have to admit. I was a bit short on time, and it's a pretty knotty subject, even for the people who work in it. But I promise that I'll come back to it and try for a from-the-bottom-up backgrounder. And I'll try to get to it before we all need life-extension drugs. What's that? You say we all need them now?

Comments (6) + TrackBacks (0) | Category: Aging and Lifespan

September 18, 2005

A Sensitive Guy

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Posted by Derek

Well, my poison ivy has abated, which is good news on several fronts. Besides the obvious one, it also means that I wasn't exhibiting a reaction to a particular reagent that I was using a lot of at the same time, an aryl isocyanate. Those are reactive little creatures, and they're known to bother some people. I'm very glad it wasn't an immune response to it, because (a) I still need to do reactions with the stuff and (b) I've never become sensitized to any lab reagent, and I'd hate to start now.

Probably the closest I've ever come was back in graduate school. I had a long synthesis that started with a tosylation reaction of a protected sugar. For the non-chemists, that's a way to convert an alcohol group into something much more reactive, and it uses a reagent called para-toluenesulfonyl chloride. Since even organic chemists don't like wandering around all day saying mouthfuls like that, it's abbreviated in the lingo as tosyl chloride.

And it reeks. It has a peculiar nasty sweetish smell, penetrating and hard to get out of your nose, particularly when you're crystallizing a kilo of the stuff. As I wrote in passing here, it was very easy to get fed up with that step. It got to the point that the smell gave me an instant headache, right up between the eyes. That's no longer the case, but I don't enjoy working with it to this day.

The other reagent that I couldn't take for a while isn't known as a sensitizer. When I was a teaching assistant during my first year, one of the sophomore organic labs was the preparation of phenyl Grignard reagent. They did that in good ol' diethyl ether, probably because it's cheap as dirt. Never mind that it's one of the most volatile (and flammable) solvents you can possibly use, and never mind that there were about two fume hoods for thirty students, so everyone just banged away out on the benchtops. The air practically got wavery with ether fumes, and why the whole place didn't go up is a real stumper.

I was teaching three lab sections a week that term, as fate would have it. After the first one, I had a headache from all that damned ether. That kicked in immediately during the second lab section the next afternoon, and I was really feeling awful by the end. Came the third section, and when the first gust of ether hit me I nearly hurled my lunch into the nearest sink. I just couldn't take it. I spent the whole afternoon teaching from out in the hall, asking people to hold up their flasks while I squinted at them and yelled encouraging advice. I only came into the lab to cruise from one side of the room to the other while holding my breath.

No, I couldn't take the smell of ether for a while after that one (it doesn't bother me now at all). But then, I spent my first week as an summer undergrad in Dale Boger's group (1982) surviving mostly on the contents of a jar of peanut butter, and it was a year or so before I could face that again, too. Academic chemistry does toughen you up.

Comments (6) + TrackBacks (0) | Category: Life in the Drug Labs

September 15, 2005

Pretty Much the Reason You'd Think

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Posted by Derek

I wrote the other day about having a hypothesis in mind when you make new drug analogs (as opposed to just trying a few to see what happens.) A colleague of mine and I were talking about this, and he offered a suggestion about why some people are much more "by the book" than others when it comes to running an analoging program. It's all, he said, about covering your anatomy.

And I think he's right. If you confine yourself to just the sorts of structures that people have had success with before, no one can question your selection. And it's also true that people who insist on a hypothesis behind every new analog also have a strong inclination toward the hypotheses that are already thought to be important (or at least fashionable.) If upper management gets convinced that the smell of your compounds is a key component for clinical success, you can expect these folks to make sure that everything gets made with the sniff test in mind.

So if you're one of these people and your project runs into the ditch - most do, you know - you're still going to be OK. You did everything the way that everyone else thinks that it should be done, and you have concrete reasons to point to if anyone asks you why a particular compound was made. It's an insurance policy.

But if you have some weird ones in there, though, or tried some things that aren't in the usual playbook, the tendency will be to blame those for anything that went wrong. Well, actually, people will blame the person who thought up or OKed these things in the first place - you. I'm not arguing that projects switch over to complete wild-blue-yonder mode, not any more than I think a pot of soup needs a pound of pepper in it. But for seasoning, I think that a drug discovery program needs a small (but real) effort to make some things just because no one's made them. These are the kinds of ideas that go on to breed new projects themselves.

I once came across an analogous effect in the financial world. An article I read about the money management industry pointed out that many fund managers tend to cluster together for safety. If everyone's going up and down roughly in tandem, there's not as much room for irate customers who demand to know why you aren't keeping up. If you buy a million dollars of IBM and it goes down, the author pointed out, people will ask "What's wrong with that IBM?" But if you buy a millions dollars worth of Zarkotronics and it tanks, people will ask "What's wrong with you?"

Comments (19) + TrackBacks (0) | Category: Who Discovers and Why

Here and There

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Posted by Derek

Work and home have conspired to leave little time for blogging for today. I'm glad that I do something easy for a living like discovering wonder drugs, rather than re-seeding my lawn full time. Crabgrass farming, on the other hand, I seem to have a natural touch for.

There are some other folks out there posting some worthwhile stuff, though. Try Orac on testimonials versus real evidence, for example. The "here's a true-life story" method of proving efficacy has never cut much ice with me, either, and it bothers me when patients line up at FDA hearings to recount their experiences with a drug up for review. Look at Iressa - it definitely helps some people, the ones with the relevant mutation, and those people will deliver an understandably passionate endorsement. But the patient population for which Iressa (and the other therapies) did nothing is not available to testify, being for the most part dead.

Teaching chemistry is the subject on another site. THe profession has been wrestling for a long time with this problem. Most students dislike chemistry when they encounter the introductory courses. Is that the fault of the subject itself, of how it's commonly taught, or is it the students themselves?

Comments (2) + TrackBacks (0) | Category:

September 13, 2005

It Pours on Ligand

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Posted by Derek

Pfizer and Ligand had their application for Oporia (lasofoxifene) shot down by the FDA this week. Details are scarce about the grounds for this action, but lasofoxifene was supposed to be one of Pfizer's string of billion-dollar drugs - you know, the ones that they need every single one of to meet their growth targets. It's a selective estrogen receptor modulator (SERM) for osteoporosis, a useful therapeutic niche which at present is pretty much owned by Lilly.

And it's a hard area to make a living in. Nuclear receptors are wonderfully interesting things, and they're wonderfully complex if you're doing basic research on them. If you're doing applied research, on the other hand, they're hideously complex - same coin, different sides. There's a large family of NRs, including the PPARs that I was speaking about a few days ago, the steroid receptors, and many other odds and ends.

They all work at the gene transcription level, and they're one of the few ways that we can mess with that world through small drug-like molecules. Many nuclear receptors can bind small molecules (like a steroid or fatty acid), and that sets off a complicated chain of events. They then often pick up another nuclear receptor protein in a sort of face-to-face binding, and that other protein one can be another of its own type or a different one. (The various retinoic acid receptors are particularly known for heterodimerizing with other members of the family.)

Then that beast picks up a number of other proteins, forming a very large complex, and this is where we lose our ability to understand what's going on. These cofactors are involved in the binding of the whole complex to stretches of DNA (a closeup view) and its subsequent readout into messenger RNA. But some of them seem to inhibit this process, and some to enhance it. To make things more interesting, the nuclear receptor complex can bind to dozens (hundreds?) of different genes, and the cofactors can switch roles (promoter, inhibitor) depending on which one they're involved with. We don't know how many different cofactors there are - a bunch, that's for sure - and different types of cells can have very different suites of them available. (Those profiles change with time and the external environment, too.) Here's an extremely well-done Flash lecture from the comprehensive NURSA site if you want to become an instant nuclear receptor nerd. I took the step several years ago, myself, when it had to be done by hand, sonny.

All this variability makes it foolhardy to generalize about nuclear receptor actions. If you say that Cofactor X is a transcriptional inhibitor, someone can come up with a system where it does the opposite. If you say that Nuclear Receptor Y is responsible for the transcriptional regulation of Gene Z, someone can show you a cell line where it has nothing to do with it, or where it does the reverse of what it does in yours. That's how the Selective Estrogen Receptor Modulators (SERMs) work. The ones you want work in opposite ways in bone tissue versus breast tissue, and if the signaling pathways were simple, that probably wouldn't be possible. This particular split seems to work through the different cofactor profile mechanism.

The complexity of the field has made some companies just throw up their hands and decide to spend their money somewhere else. For the same reasons, it's made others decide to concentrate only on that area, and Ligand is the best example. It's been quite a rough ride for them over the years. They've had (and still have) deals with several major companies, and have had all sorts of things go into development, but there haven't been any home runs yet. Worse, they're in the middle of some accounting problems (to put the matter delicately) that have led to an SEC investigation and their stock being recently delisted from NASDAQ. No, tedium has not been a big problem.

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September 12, 2005

". . .And to Furbish Falsehoods For a Magazine"

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Posted by Derek

I couldn't resist linking to this article, part of a series in the Guardian. I'm afraid that he's pretty much on target for most science stories in the news:

"Science is done by scientists, who write it up. Then a press release is written by a non-scientist, who runs it by their non-scientist boss, who then sends it to journalists without a science education who try to convey difficult new ideas to an audience of either lay people, or more likely - since they'll be the ones interested in reading the stuff - people who know their way around a t-test a lot better than any of these intermediaries. Finally, it's edited by a whole team of people who don't understand it. You can be sure that at least one person in any given "science communication" chain is just juggling words about on a page, without having the first clue what they mean, pretending they've got a proper job, their pens all lined up neatly on the desk."

As he points out, there are only a few templates available for science-based stories in the popular press - "Big Breakthrough!", "What You Thought You Knew is Wrong", and "Those Crazy Scientists" are the ones that get used the most. And let's not forget "Scientific Confirmation of (insert pre-existing bias here.)"

But, to be depressingly fair about it, there aren't many more templates for reporting any other subject. Just look at how many stories are whacked with mallets until they fit the Brave Feisty Underdog story line, or some of the others that might as well be run in italics above the stories in the newspaper or in the corner of the TV screen: Babies In Danger, How the Mighty Are Fallen, Lowlifes on Parade, Sanctimony Unmasked. There are more. Those are merely some of the non-ideological ones.

Comments (9) + TrackBacks (0) | Category: Press Coverage

September 11, 2005

Remind Me Not to Do This Again

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Posted by Derek

As I sit here typing this evening, my right arm is giving me fits. About a week ago, I had the misfortune, while retrieving a mis-thrown frisbee in the back yard with my two children, of reaching into an area with some poison ivy growing in it. And I've been paying for it ever since.

My immune system has been set off by contact with an alkylated catechol called urushiol (lot of information here.) The stuff penetrates the skin quite well, damn it all. It's simultaneously greasy (with a fifteen-carbon tail on it) and has a polar head group (the catechol), so it just wanders in there will all the other lipid molecules and does its thing. Its thing is to get oxidized to an ortho-quinone, which is probably what does the damage.

Quinones are reactive beasts, which is why we don't put catechol groups (or similar precursors) on drug structures if there's any possible way around it. Some years ago, Merck made a big splash in Science and other venues with a small molecule that affected the signaling of the insulin receptor. That was quite a feat, and worthy of the attention - but the molecule itself, derived from a natural product, was a quinone. I rolled my eyes when I first saw it, as did almost everyone else in the industry, and we were correct - Merck was never able to develop the stuff into a real drug.

A notorious exception to this rule is acetominophen, known also by its brand-name form of Tylenol, which gets metabolized to a reactive quinone-like compound. (There's no way that the compound would be seriously developed today, but that almost certainly goes for aspirin, too, and there you have one reason that it's so hard to run a drug company these days.) The acetominophen metabolite is cleared handily by one of the body's standard systems (glutathione conjugation), but if you take enough of the stuff to deplete your reserves you're in for some serious liver damage.

So, this quinone has soaked right into me and reacted with some of my cell-surface proteins, prompting my immune system to mount a big inflammatory attack. This response isn't just available in your back yard, though: it's a little-known occupational hazard in research labs. There are many classes of reactive compounds that can penetrate the skin enough to cause trouble. If a particular person's immune system finds fault with the result, they end up with dermatitis that's indistinguishable from vigorous, prolonged poison ivy contact.

A friend of mine went through this in graduate school. He had an enone derivative that he'd made before without incident, but one batch caused his forearms to redden and swell briefly. He didn't make the connection, but the next time he came through that part of the synthesis he really got the business. Realizing what was happening, he ended up passing on that step of his synthesis to someone else in the lab. His immune system had become sensitized, and it was impossible to say how bad further exposures could be.

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September 8, 2005

Muraglitazar's Turn

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Posted by Derek

There's a lot of metabolic disease news this week from the FDA. We'll get to the inhaled insulin decision next week, but I thought I'd try to catch the next one before it happens. On Friday they're reviewing the first PPAR alpha-gamma ligand to make it to the regulatory approval stage, Bristol-Meyers Squibb's unmelodious "Pargluva" (muraglitazar), which sounds more like a disease than a drug. This is a therapeutic class that everyone had great hopes for a few years ago, with most of the big players competing at full speed. In theory, this combination should help with insulin sensitivity, cholesterol, and triglycerides all at the same time, which you'd think would be just what an overweight type II diabetic patient (and there are many) might need.

But development of these compounds has been a nightmare, with bad and unexpected toxicity cropping up deep in the late-phase work. BMS (and their late-arriving partner Merck) managed to get past those rapids and through clinical trials. But their drug shows a side effect that all PPAR-gamma drug programs have had to worry about, namely edema.

They also seem to have some (perhaps related) worries about cardiovascular events, which are broken out into completely separate categories in the FDA briefing document (big PDF). That document, whopper thought it is, is worth a look if you want to see what it's like to decide whether to approve a new drug or not. I wouldn't like to have to explain it all to a lay jury, that's for sure. No doubt a few whoops and hollers, along with the occasional choked tearful expression, would help.

By my reading, the cardiovascular event profile of the drug subjects looks slightly but noticeably worse than that of the placebo group. There are plenty of possible extenuating factors, and the number of patients involved is small, but I think that this is going to be a problem for the companies during the FDA hearing. Here's the list of questions the FDA has proposed for discussion (PDF again), and you can see that edema and cardiovascular safety loom large. I can't predict which way this one is going to go, and neither can anyone else. But post-COX-2 is a bad time to be coming to the FDA with possible low-level cardiac risks in your clinical data. . .

By the way, with thousands of people involved in the clinical studies, there are bound to be some. . .unplanned adverse events. I quote without comment from the briefing document linked to above, just in case you thought (for some odd reason) that running clinical trials was easy. . .

"Subject CV168021-29-21 was a 44-year old white maile with a 3-year history of diabetes and history of overweight, hypercholesterolemia and impotence. On study day 29 the subject died as the result of a gun shot wound.

Subject CV-168006-5-3 was a 62-year old white female with a history of hypertension, smoking, and alcohol use. On study day 112 she died in a motor vehicle accident. Her car was stopped at a light when struck by a truck. The investigator considered the event not likely related to study drug."

Yes, one would, on the whole, conclude that it wasn't . . .

Comments (7) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity

September 7, 2005

The Tiniest Doors Begin to Open

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Posted by Derek

Ahmed Zewail and his group at Caltech are the kings of the very, very short time scale. For many years now, he's been using extremely short laser pulses to accomplish a long list of previously unheard-of results in spectroscopy. (A non-specialist wouldn't go far wrong by thinking of him as a molecular-scale Harold Edgerton.) His work has not gone unrecognized.

And now there's a fighting chance that he and his people have recently accomplished something that would be worthy of a second Nobel: UEM, for Ultrafast Electron Microscopy. They're taking electron microscope snapshots, one trillionth of a second at a time.

And what is this technique good for? Well, electron microscopy has long been used for imaging all sorts of materials and biological samples. Fast freezing of the samples has revealed an extraordinary amount of information in the past, and Zewail's new method basically allows this to happen in real time, at room temperature, under normal conditions. The energies required to do it aren't huge, and it's quite likely that we'll be able to get useful data without destroying delicate targets. We could end up with extreme slow-motion movies of molecular processes, imaged at electron-diffraction resolutions. We're actually going to be able to watch nanotechnology experiments as they happen.

We'd be able to see catalyst molecules moving and rearranging as they do their work, and watch the shifting environment of metal atoms inside enzyme active sites. Subtle changes in crystal structures, happening too fast for us to follow, would become clear. We could conceivably see cell membranes flex and shift as ligands bind to their embedded receptors, and see processes inside cells that no one has ever been able to observe or even suspected were there. People in completely unrelated branches of science are going to be climbing over each other to get access to these machines.

I've never met Prof. Zewail, but his paper isn't the work of a retiring personality. Its abstract states that ". . .the long sought after but hitherto unrealized quest for ultrafast electron microscopy has been realized." That's inelegantly phrased (the quest wasn't the thing that was sought after, for one thing), but I take his point. The concluding section echoes Watson and Crick, surely on purpose:

". . .even biological changes at longer times have their origin in the early atomic motions. It should be readily apparent that such dynamical evolution is critical to function. It does not escape our notice that UEM is a significant advance for this purpose. . .we foresee the emergence of new vistas in many fields, from materials science to nanoscience and biology."

No, he's not a modest man. But this discovery isn't something to be modest about. It isn't bragging if you can do what you say.

(Want more details? This is wandering off into physics, but the fast laser pulses generate electrons through the photoelectric effect. They hit the photocathode of the electron microscope, which is made of the rather exotic material lanthanum hexaboride. One of the keys to getting this to work was to use pulse energies that deliver about one electron per wave packet. That allows the microscope to focus them - Zewail points out that their earlier attempts generated larger "bunches" of electrons which were difficult to focus, and whose pulses broadened out due to the electrons repulsing each other's negative charge. The delicate touch was crucial. Of course, none of this would do much good without modern scintillators and CCD chips, which can detect single electrons after they pass through the samples. For the real fanatic, Zewail's paper is in PNAS 102, 7069.)

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September 6, 2005

Ranking the Journals - Try It at Home!

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Posted by Derek

Reader Christopher C. writes:

"In light of your recent series of postings about impact factors, I have my own questions about scientific publishing. It seems to me that in physics and chemistry the prestige of journals is more horizontal compared to biology, where there are a thousand specialty journals that are highly stratified with respect to their prestige. Now everyone knows that a paper in Nature or Science is supposed to be superb. In chemistry, it looks like even the best chemists send most of their articles to JACS, which, if my perception is correct, is not an especially prestigious journal. In biology, on the other hand, we have a strict hierarchy which is approximated by the impact factor. For molecular cell biology, I would rank them something like this, IM not-so HO:
 
Cell
Nature, Science
Genes and Development, Nature Cell Biology, EMBO J
Mol Cell Biol, J Cell Biol, PNAS
J Biol Chem
 
In my own field, which is bacterial RNA polymerase, the order is something like this:
 
Nature, Cell, Science
Molecular Cell, Nature Struct Molec Biol,
J Mol Biol, PNAS
J Biol Chem, J Bacteriol, Biochemistry
 
One could spend endless hours cataloging this for each subdiscipline. . ."

Oh, yeah. It could be useful for outsiders, too. Would readers care to submit their lists for organic chemistry journals, in order of prestige? We'll take a survey and see how closely it matchs ISI's data.

I note that each of those lists stops while still well in the "good place to publish" category - the middle and lower parts of a complete list would be harder (and more painful) to rank-order. But I couldn't have reproduced either of those orders exactly. I don't think I've ever seen or read a paper from the Journal of Bacteriology, for example, and I wouldn't have known that it was reasonably prestigious, although I have the rest of those titles covered.

In the same way, although it may not seem that way from the outside, JACS is a pretty good place to publish for a chemist. If "even the best chemists" send their work there, which is more or less true, then it's de facto harder for others to get there work in, and therefore prestigious. Science, PNAS, and especially Nature publish so little chemistry that those journals aren't really on our lists, for the most part.

But it's Angewandte Chemie that has moved definitively into first place, after some years in a rough tie with JACS. And whatever we might think about impact factors, I think we can agree that the example given in the latest issue's editorial (by Peter Goelitz, Ang. Chem 44(35) 5538) is not the way to use them. You don't come across this exact alloy of nerve and cluelessness too often. Says Goelitz:

The hankering after the high impact factor has resulted in many authors giving up a healthy amount of self criticism and sending their manuscript first to a journal in which it has no chance of being accepted. This ideology is already producing fruit as can be seen in the following: An author had a manuscript rejected from Angewandte Chemie after the assessment of three scientists. Deputy Editor Neville Compton recommended publication in the European Journal of Inorganic Chemistry (the editor of which is Karen J. Hindson) and shortly afterwards received a letter containing (this passage):

"Our manuscript was evaluated by three referees. Referee 1 finds the work is important and recommends publication (in) Angewandte Chemie (IF = 9.16) after minor revision. Referee 2 finds the scope of the work is directed to a journal such as Crystal Growth and Design (IF = 2.74). Referee 3 finds the work of high quality and compliments the authors, and feels that it would be a pity not to publish in its actual form. He or she recommends publication in Inorganic Chemistry (IF = 3.38.)

We were pleased to read that you spoke with Dr. Karen Hindson and recommended our paper for publication. However, I would like to draw your attention that if you add up the values of the Ifs of the three journals cited above and then divide by three you will obtain a value of IF = 5.09. The closest journal to this value would be Chemistry: A European Journal (IF = 4.517.) I therefore gently ask you to accept our paper. . .since you are the Editor in Chief. . ."

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Crossing Your Fingers, Authoritatively

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Posted by Derek

I recall a project earlier in my career where we'd all been beating on the same molecular series for quite a while. Many regions of the molecule had been explored, and my urge was often to leave the reservation. I put some time into extending the areas we knew about, but I wanted to go off and make something that didn't look like anything that we'd done before.

Which I did sometimes, and then I'd often get asked: "Why did you make that compound?" My answer was simply "Because no one had ever messed with that area before, and I wanted to see what would happen." Reactions to that approach varied. Some folks found that a perfectly reasonable answer, sufficient by itself. Others didn't care for it much. "You have to have a hypothesis in mind," they'd say. "Are you trying to improve the pharmacokinetics? Fix a metabolic problem? Pick up a binding interaction that you think is out there in the XYZ loop of the protein? You can't just. . .make stuff."

I respected the people in that first group a lot more than I did the ones in the second. I thought then, and think now, that you can just go make stuff. In fact, you not only can, but you should. You probably don't want to spend all your time doing that, but if you never do it at all, you're going to miss the best surprises.

I take issue with the idea that there has to be a specific hypothesis behind every compound. That supposes amounts of knowledge that we just don't have. Most of the time, we don't know why our PK is acting weird, and we're not sure about the metabolic fate of the compounds. And we sure don't know their binding mode well enough to sit at our desks and talk about what amino acids in the protein backbone we're reaching out for. (OK, if you've got half a dozen X-ray structures of your ligands bound in the active site of your target, you have a much better idea. But if your next compound breaks new structural ground, off you may well go into a different binding mode, and half your presuppositions will go, too.)

I like to think that I've come to realize just how ignorant I am in issues of drug discovery. (In case you have any doubt, I'm very ignorant indeed.) But I still hear people confidently sizing up new analog ideas on the blackboard, though: No, that one won't bind well in the Whoozat region. Doesn't have the right spacing. And that one should be able to reach out to that hydrophobic pocket we all know about. Let's make that one first. (These folks are talking without X-ray structures in hand, mind you.)

Well, if it makes you feel better, then go ahead, I suppose. But this kind of thing is one tiny step up from lucky rabbit feet, for which there is still a market.

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September 1, 2005

Thought For a Long Weekend

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Posted by Derek

Many of my readers here are scientists, and it's fair to say that everyone who stops by regularly must have an interest in the subject. It's easy to forget that scientific research is (like many other things) one of the brightly colored dabs of paint that make up the very thin veneer we call civilization.

There's a lot of stuff underneath, and a lot of it is ugly. It's the Hobbesian state of nature down there, a struggle for food and water and territory. Being able to think all day for a living - well, that's a huge outlier exception to the way the vast majority of human beings have had to live their lives. What's happened to New Orleans has been a terrible reminder of this truth. It's taken just a few days for the Lord of the Flies to become mayor in a special election there, and the same thing could happen anywhere else on Earth.

Let's hope that it never happens to us. Be grateful that you have the weekend to enjoy in peace and sanity, and consider giving something to help pull those people out of the water, out of the mud, and back to the dry land of the 21st century. I've given to the American Red Cross, and there's a list of other suggestions here. I'll see everyone on Tuesday.

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