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Home > Weblog Columns > In the PipelineWeblog columns [select a blog][Corante Blog]BETWEENLAWYERS: technology + culture + lawBRAINWAVES:neurons, bits & genesCOPYFIGHT: thepolitics of intellectual propertyGOYAMI: search engine marketingIDEAFLOW:creativity+ innovationIN THEPIPELINE: drugdiscoveryMANY-TO-MANY: socialsoftwareREBUILDINGMEDIA: the economics of mediaSTRANGE ATTRACTOR:social mediaTOTALEXPERIENCE: experience designAbout this Author 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.comChemistry and Pharma Blogs:PharmalotOrg Prep DailyOn PharmaOne in Ten ThousandAway From the BenchQDIS BlogChemical MusingsIn Vivo BlogThe ChemblogMolecule of the DayKinase ProDrugs and PoisonsJungfreudlichChembarkSocial DetritusPharmagossipWhistling in the WindOrganometallic CurrentGreat Molecular CrapshootPost Doc Ergo Propter DocA Chemist's Lab NotebookThe Curious Wavefunction
October 13, 2008Old School - Really Old Posted by DerekWe try to be delicate when we synthesize our molecules – really, we don. Delicate reactions often have better yields and fewer side products. Exotic catalysts in perfectly tuned metal coupling reactions – these things are wonderful when they work, because you go from pure starting material to darn near pure product.But life in the drug labs is not always thus. We also have to turn back the clock, and break out reactions that our grandfathers would have recognized – dark, fuming things that will eat a hole in your lab coat. Nitration is one of these – good old nitric acid is still very much around for that reaction, often in vile mixtures with sulfuric and the like. It’s cheap, and it often works, so you can’t get away from it. And if 1:1 nitric/sulfuric won’t perforate your clothing, you must have put on armor instead of Armani. Chlorosulfonic acid is another such reagent. It’s nasty by anyone’s standards, but it’ll stick a chlorosulfonyl group onto an activated aromatic ring in one step, which is nothing to take lightly. You don’t want to pour that into water to work it up, not unless you want to see it splatter all over your hood. Nope, you’ll need a trip to the ice machine – slow drizzling over crushed ice is the traditional workup, for good reason.That’s a good acid for another brute-force reaction that we still have with us: the Friedel-Crafts. Fancier ways exist to acylate an aromatic ring – those metal-catalyzed ones, for example, often in the presence of carbon monoxide. But who wants to use CO if you don’t have to? And you need a leaving group where the acyl group is going to go. The Friedel-Crafts will just come in and jam one in on an unsubstituted carbon, if the electronics of the ring are right. And all you need to do is treat your molecule with some hammer-of-the-gods reagent like chlorosulfonic acid, polyphosphoric acid (which looks and acts like honey from Hell), or straight aluminum chloride powder. That last one is at least a solid, albeit a corrosive one, but you pay the toll during the workup. That’s when it hydrolyzes to piles of white aluminum oxide junk, often turning your reaction into a thick mess.So no, it’s not all twenty-first chemistry, all the time. World War I-era chemistry is still very much with us at times. Actually, I sort of like it that way. When I have to break out the polyphosphoric acid, the powdered iron, or the elemental bromine, I feel as if I’m keeping faith with my predecessors. They wouldn’t know what to make of the LC/mass spec machine, but they’d grin when they saw me trying to work up my aluminum chloride reactions.Comments (0) + TrackBacks (0) | Category: Life in the Drug Labs October 10, 2008Kevin Trudeau: A Bit of Good NewsPosted by DerekI thought, given all the recent news, that everyone could use a story that would bring a smile to their faces, so here we go: Kevin Trudeau, the infomercial king who makes his living slandering drug research and feeding conspiracy theories about diet and health, has been fined $5 million dollars over the marketing of his weight-loss book. He's also been banned from the infomercial business for three years, and found in contempt of court.The judge in the case, clearly exasperated, called Trudeau "not a reliable witness" and said that he had "clearly, and no doubt intentionally" violated a 2004 order to restrain from deceptive marketing practices. To give you an idea, Trudeau stated repeatedly that his weight-loss plan involved no exercise, and could be completed easily at home. Lucky customers who sent in their money found that the plan included an hour of walking a day, and that it involved colonic cleansing, injections of human growth hormone, and that the last phase of the plan was stated to go on for the rest of their lives.Hey, walking an hour a day is good advice, but you don't have to send money to some guy (who tells you that it isn't exercise) to find out about it. And that seems to describe his books pretty well: a mixture of obvious, well-known advice and lunacy, served up at the highest price the market will bear, over and over. If you want to get the Full Trudeau, this Washington Post profile from 2005 will be your window into his wonderful world - it starts with the electromagnetic chaos eliminator necklace he wears, which he says keeps his brain from being microwaved, and goes on from there. Is anyone surprised that he also recommends Scientology?With any luck, this charlatan will be off the airwaves for a few years - or, if he reappears, perhaps we can all hope for a jail term next time. I'll cheer. After all, this is a person who goes around telling people that drug researches like me are deliberately poisoning millions of people and withholding cures. Whatever he has coming to him is fine with me.Comments (23) + TrackBacks (0) | Category: October 9, 2008More Glowing Cells: Chemistry Comes Through AgainPosted by DerekI’ve spoken before about the acetylene-azide “click” reaction popularized by Barry Sharpless and his co-workers out at Scripps. This has been taken up by the chemical biology field in a big way, and all sorts of ingenious applications are starting to emerge. The tight, specific ligation reaction that forms the triazole lets you modify biomolecules with minimal disruption (by hanging an azide or acetylene from them, both rather small groups), and tag them later on in a very controlled way.Adrian Salic and co-worker Cindy Yao have just reported an impressive example. They’ve been looking at ethynyluracil (EU), the acetylene-modified form of the ubiquitous nucleotide found in RNA. If you feed this to living organisms, they take it up just as if it were uracil, and incorporate it into their RNA. (It’s uracil-like enough to not be taken up into DNA, as they’ve shown by control experiments). Exposing cells or tissue samples later on to a fluorescent-tagged azide (and the copper catalyst needed for quick triazole formation) lets you light up all the RNA in sight. You can choose the timing, the tissue, and your other parameters as you wish.For example, Salic and Yao have exposed cultured cells to EU for varying lengths of time, and watched the time course of transcription. Even ten minutes of EU exposure is enough to see the nuclei start to light up, and a half hour clearly shows plenty of incoporation into RNA, with the cytoplasm starting to show as well. (The signal increases strongly over the first three hours or so, and then more slowly).Isolating the RNA and looking at it with LC/MS lets you calibrate your fluorescence assays, and also check to see just how much EU is getting taken up. Overall, after a 24-hour exposure to the acetylene uracil, it looks like about one out of every 35 uracils in the total RNA content has been replaced with the label. There’s a bit less in the RNA species produced by the RNAPol1 enzyme as compared to the others, interestingly.There are some other tricks you can run with this system. If you expose the cells for 3 hours, then wash the EU out of the medium and let them continue growing under normal conditions, you can watch the labeled RNA disappear as it turns over. As it turns out, most of it drops out of the nucleus during the first hour, while the cytoplasmic RNA seems to have a longer lifetime. If you expose the cells to EU for 24 hours, though, the nuclear fluorescence is still visible – barely – after 24 hours of washout, but the cytoplasmic RNA fluorescence never really goes away at all. There seems to be some stable RNA species out there – what exactly that is, we don’t know yet.Finally, the authors tried this out on whole animals. Injecting a mouse with EU and harvesting organs five hours later gave some very interesting results. It worked wonderfully - whole tissue slices could be examined, as well as individual cells. Every organ they checked showed nuclear staining, at the very least. Some of the really transcriptionally active populations (hepatocytes, kidney tubules, and the crypt cells in the small intestine) were lit up very brightly indeed. Oddly, the most intense staining was in the spleen. What appear to be lymphocytes glowed powerfully, but other areas next to them were almost completely dark. The reason for this is unknown, and that’s very good news indeed. That’s because when you come up with a new technique, you want it to tell you things that you didn’t know before. If it just does a better or more convenient job of telling you what you could have found out, that’s still OK, but it’s definitely second best. (And, naturally, if it just tells you what you already knew with the same amount of work, you’ve wasted your time). Clearly, this click-RNA method is telling us a lot of things that we don’t understand yet, and the variety of experiments that can be done with it has barely been sampled.Closely related to this work is what’s going on in Carolyn Bertozzi’s lab in Berkeley. She’s gone a step further, getting rid of the copper catalyst for the triazole-forming reaction by ingeniously making strained, reactive acetylenes. They’ll spontaneously react if they see a nearby azide, but they’re still inert enough to be compatible with biomolecules. In a recent Science paper, her group reports feeded azide-substituted galactosamine to developing zebrafish. That amino sugar is well known to be used in the synthesis of glycoproteins, and the zebrafish embryos seemed to have no problem accepting the azide variant as a building block.And they were able to run these same sorts of experiments – exposing the embryos to different concentrations of azido sugar, for different times, with different washout periods before labeling all gave a wealth of information about the development of mucin-type glycans. Using differently labled fluorescent acetylene reagents, they could stain different populations of glycan, and watch time courses and developmental trafficking – that’s the source of the spectacular images shown. Losing the copper step is convenient, and also opens up possibilities for doing these reactions inside living cells (which is definitely something that Bertozzi’s lab is working on). The number of experiments you can imagine is staggering – here, I’ll do one off the top of my head to give you the idea. Azide-containing amino acids can be incorporated at specific places in bacterial proteins – here’s one where they replaced a phenylalanine in urate oxidase with para-azidophenylalanine. Can that be done in larger, more tractable cells? If so, why not try that on some proteins of interest – there are thousands of possibilities – then micro-inject one of the Bertozzi acetylene fluorescence reagents? Watching that diffuse through the cell, lighting things up as it found azide to react with would surely be of interest – wouldn’t it?I’m writing about this the day after the green fluorescent protein Nobel for a reason, of course. This is a similar approach, but taken down to the size of individual molecules – you can’t label uracil with GFP and expect it to be taken up into RNA, that’s for sure. Advances in labeling and detection are one of the main things driving biology these days, and this will just accelerate things. (It’s also killing off a lot of traditional radioactive isotope labeling work, too, not that anyone’s going to miss it). For the foreseeable future, we’re going to be bombarded with more information than we know what to do with. It’ll be great – enjoy it!Comments (5) + TrackBacks (0) | Category: Analytical Chemistry | Biological News October 8, 2008A Green Fluorescent Nobel PrizePosted by DerekSo it was green fluorescent protein after all! We can argue about whether this was a pure chemistry prize or another quasi-biology one, but either way, the award is a strong one. So, what is the stuff and what’s it do?Osamu Shimomura discovered the actual protein back in 1962, isolating it from the jellyfish Aequoria victoria. These were known to be luminescent creatures, but when the light-emitting protein was found (named aequorin), it turned out to give off blue light. That was strange, since the jellyfish were known for their green color. Shimomura then isolated another protein from the same jellyfish cells, which turned out to absorb the blue light from aequorin very efficiently and then fluoresce in the green: green fluorescent protein. The two proteins are a coupled system, an excellent example of a phenomenon known as FRET (fluorescence resonance energy transfer), which has been engineered into many other useful applications over the years.Fluorescence is much more common in inorganic salts and small organic molecules, and at first it was a puzzle how a protein could emit light in the same way. As it turns out, there’s a three-amino-acid sequence right in the middle of its structure (serine-tyrosine-glycine) that condenses with itself when the protein is folded properly and makes a new fluorescent species. (The last step of the process is reaction with ambient oxygen). The protein has a very pronounced barrel shape to it, and lines up these key amino acids in just the orientation needed for the reaction to go at a reasonable rate (on a time scale of tens of minutes at room temperature). This is well worked out now, but it was definitely not obvious at the time.In the late 1980s, for example, the gene for GFP was cloned by Doug Prasher, but he and his co-workers believed that they could well express a non-fluorescent protein that would need activation by some other system. He had the idea that this could be used as a tag for other proteins, but was never able to get to the point of demonstrating it, and will join the list of people who were on the trail of a Nobel discovery but never quite got there. Update: Here's what Prasher is doing now - this is a hard-luck story if I've ever heard one Prasher furnished some of the clone to Martin Chalfie at Columbia, who got it to express in E. coli and found that the bacteria indeed glowed bright green. (Other groups were trying the same thing, but the expression was a bit tricky at the time). The next step was to express it in the roundworm C. elegans (naturally enough, since Chalfie had worked with Sydney Brenner). Splicing it in behind a specific promoter caused the GFP to express in definite patterns in the worms, just as expected. This all suggested that the protein was fluorescing on its own, and could do the same in all sorts of organisms under all sorts of conditions.And so it’s proved. GFP is wonderful stuff for marking proteins in living systems. Its sequence can be fused on to many other proteins without disturbing their function, it folds up just fine with no help to its active form, and it’s bright and very photoefficient. Where Roger Tsien enters the picture is in extending this idea to a whole family of proteins. Tsien worked out the last details of the fluorescent structure, showing that oxygen is needed for the last step. He and his group then set out to make mutant forms of the protein, changing the color of its fluorescence and other properties. He’s done the same thing with a red fluorescent protein from coral, and this work (which continues in labs all over the world) has led to a wide variety of in vivo fluorescent tags, which can be made to perform a huge number of useful tricks. They can sense calcium levels or the presence of various metabolites, fluoresce only when they come into contact with another specifically labeled protein, used in various time-resolved techniques to monitor the speed of protein trafficking, and who knows what else. A lot of what we’ve learned in the last fifteen years about the behavior of real proteins in living cells has come out of this work – the prize is well deserved.I want to close with a bit of an interview with Martin Chalfie, which is an excellent insight into how things like this get discovered (or don't!)Considering how significant GFP has been, why do you think no one else came up with it, while you were waiting for Doug Prasher to clone it?"That’s a very important point. In hindsight, you wonder why 50 billion people weren’t working on this. But I think the field of bioluminescence or, in general, the research done on organisms and biological problems that have no immediate medical implications, was not viewed as being important science. People were working on this, but it was slow and tedious work, and getting enough protein from jellyfish required rather long hours at the lab. They had to devise ways of isolating the cells that were bioluminescent and then grinding them up and doing the extraction on them. It’s not like ordering a bunch of mice and getting livers out and doing an experiment. It was all rather arduous. It’s quite remarkable that it was done at all. It was mostly biochemists doing it, and they were not getting a lot of support. In fact, as I remember it, Doug Prasher had some funding initially from the American Cancer Society, and when that dried up he could not get grants to pursue the work. I never applied for a grant to do the original GFP research. Granting agencies would have wanted to see preliminary data and the work was outside my main research program. GFP is really an example of something very useful coming from a far-outside-the-mainstream source. And because this was coming from a non-model-organism system, these jellyfish found off the west coast of the U.S., people were not jumping at the chance to go out and isolate RNAs and make cDNAs from them. So we’re not talking about a field that was highly populated. It was not something that was widely talked about. At the time, there was a lot of excitement about molecular biology, but this was biochemistry. The discovery really was somewhat orthogonal to the mainstream of biological research."Here's an entire site dedicated to the GFP story, full of illustrations and details. That interview with Chalfie is here, with some background on his part in the discovery. Science background from the Nobel Foundation is here (PDF), for those who want even more).Comments (32) + TrackBacks (0) | Category: Biological News | Current Events October 7, 2008Nobel Season 2008Posted by DerekSo we come upon Nobel season again. As I do every year, I'm going to throw the comments section open for nominations for who should (and who shouldn't!) get the prize in Chemistry this year. We may well have a trapdoor open on us again, since some years the committee uses the Chemistry prize as a dumping ground for spare biology prizes, but we'll see how it goes.If we do get a chemistry prize this time, my money is against my own field, synthetic organic chemistry. In fact, long-term, I'm betting against it, unless the work has a hook into some broader story. That could be nanotechnology, drug discovery (wouldn't that be nice?), advances in materials science, energy storage or conversion, and the like. But I don't see many (any?) prizes being given out for straight organic synthesis, the way E. J. Corey's was. I think that the time for that has indeed passed.But there's room for a prize or two in synthetic methods, I have to say, a sort of H. C. Brown-type prize. A lot of people have waited to see if palladium couplings would get one, for example. I think that metal-catalyzed couplings are definitely worthy of the recognition - they've taken over the world to a degree that younger chemists can't realize - but I don't know if the Nobel committee has ever been able to unravel the prize distribution to where they feel safe with it.That's a problem in several areas (drug discovery being another example where credit is often spread around). Individual researchers can end up in the same boat, which is the usual opinion about, say, George Whitesides of Harvard. He's done a lot of very interesting work over the years, but it's been in several rather different areas. I think we can use all of those sorts of scientists we can get, myself, but the profile doesn't match up well with what the Nobel folks are looking for.So, place your bets, folks. For reference, the Thomson/Reuters folks have a short list of their own, based on literature citations: Charles Leiber of Harvard for nanotech, Roger Tsien of UCSD for green fluorescent protein, and Krzysztof Matyjaszewski of Carnegie Mellon for atom-transfer radical polymerization.Comments (20) + TrackBacks (0) | Category: Current Events October 6, 2008Imclone Really Does Get BoughtPosted by DerekWell, it looks as if I'll finally be able to stop talking about Imclone: the word came out this morning that they've agreed to a $70/share deal with Lilly. Some thoughts on this:1. I would still like to know how the uncertainty around the Erbitux follow-up antibody is supposed to be resolved. It's hard for me to make sense of this for Lilly unless they think that they can get substantial revenue from it, and Bristol-Myers Squibb presumably will disagree with their projected figures. None of the news stories so far have addressed this issue, and I presume that it's going to be a matter for negotiations (or for the courts, if it comes to that).2. It seems that some analysts are seeing this deal as a sign of weakness in Lilly's pipeline, perhaps signaling that Effient (prasugrel) might be delayed more or labeled so restrictively that it has no chance of living up to expectations. We'll see how Lilly's stock performs today, and read the mood of its investors.3. Well, Carl Icahn really did have something up his sleeve. Considering what Imclone was trading at before all this, he has plenty of reasons to be happy. But now will he turn his attention to Biogen again, and try to do the same thing with (or to) them?4. I stand corrected! I had trouble believing that someone would come in at this price under these conditions, but, well, here they are. I should keep in mind that a fair number of mergers and acquisitions in this industry seem problematic (or downright senseless) to me, and adjust accordingly.Comments (6) + TrackBacks (0) | Category: Business and Markets October 3, 2008Day OffPosted by DerekNo time for a post this morning, unfortunately. The arguments are continuing full speed in the comments to Hard Times: A Manifesto, though, and I plan to do a long-overdue blogroll update this weekend. There are several sites that have needed to be added for quite a while now, and several others that have fallen into inactivity.Inactivity doesn't seem to be a problem around here, anyway - today's an exception! Have a good weekend, and I'll see everyone on Monday.Comments (2) + TrackBacks (0) | Category: Blog Housekeeping October 2, 2008Taranabant Is No MorePosted by DerekMerck has taken a step that many people have been expecting, and announced that they are no longer developing taranabant, their cannabinoid antagonist (or is it an inverse agonist?)I'd expressed grave doubts about the drug earlier this year, which turned out to be well-founded. That latter post included the line "I don't see how they can get this compound through the FDA", and now Merck seems to have come to the same conclusion. Further clinical data seem to have shown far too many psychiatric side effects (anxiety, depression, and so on), which increased along with the dose of the drug.The cannabinoid antagonist field has already experienced a crisis of confidence after Sanofi-Aventis's rimonabant failed to gain approval in the US. This latest news should ensure that no company tries to develop one of these drugs until we've learned a great deal more about their pharmacology. Given how little we know about the mechanisms of these mental processes, though, that could take a long, long time. We can pull the curtain over this area, I think.Comments (10) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | The Central Nervous System | Toxicology Eli Lilly and Imclone: Sensible? Real?Posted by DerekWord leaked out yesterday that Imclone’s secret bidder is Eli Lilly. Well, let’s revise that – so far, Lilly hasn’t made a bid for the company. And that’s the first thought I had about this business: isn’t it taking quite a while? You’ll recall that Carl Icahn told Bristol-Myers Squibb a couple of weeks ago that he’d been in talks with someone else. Then we were going to hear about it over the weekend. Then the name would be revealed Wednesday at midnight (of all times). Now here we are on Thursday with no official announcement.And the delay probably doesn’t have anything to do with the situation in the credit markets, because Icahn has been sure to emphasize that the deal he’s looking at is not subject to financing. That means all this extra time is probably due to good old caution – and I don’t blame Lilly for mulling things over. There are plenty of reasons to wonder if Imclone is worth the money for an outside company, given its status with BMS. This clearly isn’t the instant-winner operators-are-standing-by deal that Imclone would like to have us believe it is.Does a Lilly deal make sense? It might, if they could be sure that they were going to get the Erbitux follow-up. But I’m willing to bet that this is exactly the issue that things are stuck on, since BMS believes (with reason) that they have a share of it, and won’t give it up easily. And I’d be willing to see this go through, even at a ruinous price, if it would get Carl Icahn out of the drug industry. But no such luck, I’m afraid. He’s probably still eyeing Biogen, and who knows who else. I spent some time yesterday going on about how we shouldn’t blame evil MBA types for the problems in our business, but Icahn is the sort of guy I’m nearly willing to make an exception for. A pure dealmaker, I don’t see him as someone who understands scientific research or who has the patience for it. If we’re going to point the finger at managers whose only goals seem to be to make the quarterly numbers and pump up the stock price, he’s as good an example as I can think of. A dose of this stuff is exactly what we don’t need at the moment.One more consideration: who leaked Lilly’s name, anyway? The Wall Street Journal seems to have been the first with the story, quoting "people familiar with the matter". Well, cui bono? Who has an interest in moving it along and showing that it’s a real possibility, in getting possible bidders to feel some pressure? Who indeed?Comments (5) + TrackBacks (0) | Category: Business and Markets October 1, 2008Hard Times: A ManifestoPosted by DerekThe more I think about all the research layoffs that have been going on for the last year or two around the industry, the more I think that we really are seeing a change in the way drug discovery is being done.Most of the jobs have been lost from the large companies. There have, of course, been shutdowns at the smaller ones, but I don’t think that those have been running at any different rate than usual. Startups and other smaller shops are always rearranging as their skills, finances, and luck dictate – that seems to be going on at the usual pace. But what’s different is the wave after wave of job cuts at the Pfizers, GSKs, AstraZenecas, J&Js – the big hitters (and big employers) of the industry. Even the companies that haven’t had major layoffs (Novartis comes to mind) aren’t exactly hiring heavily.So what’s going on? My take is still that this is a shift – as far as the US end is concerned – from larger research outfits to smaller ones. After all, the drugs are going to have to come from somewhere, and the deal-making for small companies that have something promising has been intense. It just seems that the larger companies don’t think that they can do as much of this discovery work themselves – not, at least, at the prices that make sense.Now, it’s true that a lot of chemistry has been outsourced to contractors in India and China, and that several firms have opened research divisions of their own overseas. That’s a cost-cutting move, too, certainly – but look at what this says about research here in the US. Everyone knows – including the people in Shanghai and Hyderabad – that the difficult, high-level research is still not being done there. That’ll change, as the human and physical infrastructure improves, but the bulk of the outsourced chemistry is methyl-ethyl-butyl-futile stuff. It’s “Hey, make me a library based on this scaffold structure” or “Hey, make me fifty grams of this intermediate”.This kind of thing is definitely cheaper to do outside the country. It’s not always as timely as it should be, or as well-done – so it’s not as cheap as it always looks. But overall, on the average, you can bang out compounds for less money by outsourcing. That’s not going to change, either. The countries that furnish the services may change, as time goes on. But until the whole world is a high-wage environment (or, more horribly, until the only countries that aren’t are so benighted that no such work can be done there), ordinary chemistry is going to be done where it can be done for the least money.So what’s left for us here in the US? The hard stuff. The risky stuff. The science that needs well-paid experienced people hovering over it the whole time. The cheaper, easier research is leaving – a lot of it has left already. We get to take on the stuff that can’t be outsourced.And that’s why I think that there’s a shift to smaller firms. They’re traditionally the risk-takers in this business, and I think that’s going to be more true than ever. The larger companies, to me, seem to be trying to play it safer than ever. They have huge costs to meet, and don’t seem to think that they can devote as much of their resources to taking chances. We can argue about whether’s that’s wise (after all, you might think that larger companies with more cash might be the ones who could afford more risk). But that’s not how it’s been working – not for quite a while, when you think about it.Here’s the hard part: the world does not owe any of us a high-paying research job. Neither the world, nor the US government or the US pharma industry owe us jobs of any kind. I wish that that weren’t true, but it most certainly is. Those of us trying to make a living through science and drug discovery are going to have to scramble for it. We’re going to have to prove our worth to those who are in a position to pay for us, and we’re going to have to try to make as many of our own opportunities as we can.There are some things that can help us out in this period (see below), and there are some others that will do none of us any good at all. I know from some of the comments here that not all of you will agree with this, but as far as I’m concerned, here are some of the no-good-whatsoever moves:1. Complaining about the Evil Suits Who Are Ruining the Industry. Look, I’ve been unemployed in this business, too. A merger pitched several hundred of us out into the market when our entire site was shut down. But I didn’t think that it was being done because upper management was enjoying it. They were, as far as I can tell, trying to keep the company going while having it make as much money as possible – the same behavior that had been paying my salary, actually. The constant drive to do those things is what’s paid all our salaries. Now, that doesn’t mean that upper management is always right. I didn’t say that they couldn’t be stupid (hey, I’ve sat through some of those presentations, too). I’m just saying that they’re not evil. Ranting about it is a pointless distraction from the business of keeping your job or getting another one. And besides, if they really are making a stupid mistake, that creates opportunities later on (see below).2. Complaining about All Those Foreigners. I have even less time for this one. As far as outsourcing goes, I don’t see how I can tell chemists in China not to do the same work as American chemists for less money. (We should be making sure that we’re not doing the same work – see below). This is how economies grow, and how the world improves. I’m living in one of the greatest places in the world, and have been making a better living than most of the world’s population: I have no room to tell someone that they can’t try to reach for the same standard of living.And as for foreign scientists working here, well, I think that one of the reasons I’ve been living in one of the greatest places in the world is that it’s been a haven for all sorts of bright, hard-working people. We’re not going to turn this into an immigration blog – there’s lots of room to argue about our current policies, particularly regarding unskilled laborers. But that’s not what we’re dealing with in the sciences. As far as I can see, we can use all the intelligent, creative, entrepreneurial people we can take, and we need to make sure that our country is the kind of place that people like that aspire to live in. So if those don’t do any good, what does? Well, look at the situation. This is, as I’ve said before, a terrible time to be an ordinary chemist in this industry. That goes for the ordinary biologists, too. We’ve all got to demonstrate why we’re worth what we want to earn, and doing something that can be done for half the price somewhere else isn’t going to cut it.So improve your skills. Learn new techniques, especially the ones that are just coming out and haven’t percolated down to the crank-it-out shops in the low-wage countries. Stay on top of the latest stuff, take on tough assignments. Keeping your head down in times like these will move you into the crowd that looks like it can be safely let go.That’s one thing. Another one is the traditional advice given in all industries: keep in touch with everyone you know around the business. Use networking sites, keep current phone numbers, drop people an e-mail now and then. Getting laid off may well have had nothing to do with what you did – but finding a new job will have everything to do with it. If you don’t have any contacts around the business, large outfits and small, you’re going to have a harder time of it for sure.And finally, here’s a more macro-scale suggestion. We medicinal chemists need to think more about being the source of startup companies ourselves. That’s harder to do if you’re part of a service group, or if you have that mentality. If your job is to crank out molecules, then you need to find a place that needs someone to do that. But if you’ve got a larger skill set, it may be large enough to get together with some other creative people and try to get some funding for ideas that no one else is doing. People still need medicines, and as long as we can still discover them here, it sure beats waiting for the phone to ring. If the bigger companies are in fact making a mistake by cutting research, what better revenge than to make them wish they hadn’t?Comments (99) + TrackBacks (0) | Category: Business and Markets September 30, 2008Various Drug Industry News, None of It All That GoodPosted by DerekToday brings the news of which areas Pfizer has decided to bail out of: obesity, most cardiovascular (it seems), anemia, osteoporosis and some osteoarthritis, liver disease, and muscle. They're concentrating on oncology, pain, Alzheimer's, and diabetes, which the company seems to have identified as the best intersection of their pipeline and the associated profits.This will probably fuel speculation that the company is Imclone's mystery bidder - that name will supposedly be revealed at midnight on Wednesday, if I'm reading these reports correctly. If so, that makes me want to groan and roll my eyes. I'm waiting for Carl Icahn to tell everyone that they'll have to say the secret password to find out.That news item linked to above also mentions that Pfizer has shed ten thousand employees since January of last year. Yikes. And on that subject, I hear from several sources that GlaxoSmithKline is cutting preclinical development hard today. People seem to have known that it was coming today, and roughly how bad it would be, but today is supposedly the day that names are read off the list. Good luck to people there. The contractions continue.There's no longer any doubt, in case anyone was wondering, that this is the worst stretch for research employment at the big pharmaceutical companies in at least twenty years (to my certain knowledge) and very likely much longer than that, from what longer-serving colleagues tell me. Frankly, I'm not sure we've ever seen anything quite like this - which makes further prediction impossible. . .Comments (53) + TrackBacks (0) | Category: Business and Markets September 29, 2008Why Don't You Just. . .Posted by DerekFor the most part, the biologists on a drug discovery project expect us in the med-chem labs to be able to make pretty much anything we need to make. Actually, I don’t have to go that far – the other chemists more or less expect that, too. Chemistry’s a big field, with a lot of reactions and techniques, and if you want some particular structure badly enough, there are usually ways to get to it.But not always, and not always by routes that you’re willing to put up with. That’s especially true early in a project when you need some robust chemistry to turn out a lot of diverse analogs quickly, so you can have some idea of which parts of the molecule are most important. Synthetic trouble at this stage is frustrating for everyone involved.I was on a project a few years ago that ran into this exact problem. Compounding the pain was the way the lead compound looked when it was up on a screen during a meeting: small, perfectly reasonable, easy to deal with. Hah! It was a werewolf, that thing. None of the ideas that we had ever worked out the first time, and many of them never worked out the last time, either. Meeting after meeting would take the same format when there were outside managers or other chemists present: “But why don’t you just. . .” “We did. It doesn’t work.” “But then you should try. . .” “We know. We tried that. It doesn’t work.” “Well, OK, but then you could always come around and. . .” “We could. If it worked. But it doesn’t.”New chemists would be added on to the program to try to get things moving, and they’d always come in rolling up their sleeves, muttering “Do I have to do everything myself around here. . .” How do I know? Because I was one of them. Within a month or two, though, I was in the same shape as everyone else on the project, looking at a bunch of NMRs and mass spec traces and trying to figure out what went wrong. Meanwhile, helpful folks would wander past the whiteboard and ask me how come we hadn’t tried the reaction that had just failed for the eleventh time. Eventually we learned to offer the more persistent questioners a supply of our starting material so they could solve the problem themselves and be heroic, but nothing ever came of that.The project managed to stagger to a clinical candidate, but ran into mechanistic problems in the more advanced animal models. (That was really the hot fudge topping on the whole sundae – this was one of those therapeutic areas whose definitive animal models were too complex and costly to run until you were absolutely sure you had The Compound). I haven’t run into one quite like this since, and with any luck, I never will.Comments (14) + TrackBacks (0) | Category: Life in the Drug Labs September 26, 2008Prasugrel Today?Posted by DerekI wrote back in the summer about the FDA's delayed decision on Lilly's potential anticoagulant blockbuster Effient (prasugrel). Well, those three months have zipped right by, and the agency is supposed to rule today.Prediction, for what it's worth: I think the drug will be approved, but with label restrictions for the group(s) that seemed to respond best to it in trials - who may have been. at least partly, the groups that could put up with the associated bleeding the best, too. So no elderly patients, no low-weight ones, and no one with a history of stroke or TIA. That'll cut down the market for the drug, definitely, but not as much as if it doesn't get approved at all, right? I think the FDA will require Lilly to keep a careful eye on how Prasugrel performs in the real world while they wait on the results of the next trial to come in, with a possible label-language change to come at that point.I'll give that option about a 70% chance. The 30% chance is that they delay things yet again, since the agency has been in a delaying risk-averse mood these days. We'll know soon. This new policy of not issuing those irritating "approvable" letters has made this sort of thing rather more tense, hasn't it?Comments (5) + TrackBacks (0) | Category: Cardiovascular Disease | Regulatory Affairs Imclone's Secret AdmirerPosted by DerekSo it seems that Bristol-Myers Squibb took my advice (yeah, sure) and made an insultingly incremental counteroffer for Imclone, raising their $60/share all the way to. . .$62. I was hoping for something more like $60.25 myself, but you can’t have everything. (I should send them a bill for consulting services and see how far that gets me).Carl Icahn has replied in yet another public letter, saying that there must be more productive ways for BMS to enrich its lawyers. I notice that the folks at the Wall Street Journal’s Health Blog are getting tired of the extended correspondence between Icahn and BMS’s Jim Cornelius. Although I’m still enjoying the show, I can see where it will eventually pall.Icahn claims that his mystery $70/share bidder is doing due diligence, which should be completed this weekend. You’d think that any due diligence worth the name would tell someone not to pay $70/share for Imclone while Erbitux is still tied up with Bristol-Myers Squibb and its successor’s status is still very much in doubt. Wouldn’t you? Just how long does it take to run those numbers, anyway? Especially in this financial market, with credit tightening and the investment banking community in chaos? Or is the whole thing just a load of. . .no, no, Carl Icahn wouldn’t stoop to tactics like that. And I am Marie of Rumania.My prediction: 64% chance that the companies agree, with much face-saving theater, at a price of about $65 per share. 35% chance that the whole business falls apart for now, due to the uncertainly about IMC-11F8. And that leftover 1% chance is that there really is a $70/share bidder.Comments (4) + TrackBacks (0) | Category: Business and Markets September 25, 2008Pfizer: As We Speak?Posted by DerekI'm hearing reports that Pfizer is telling employees in various therapeutic areas right now that there will be deep cuts coming, and that more details will be coming out in about two weeks (individual-level layoff notices, etc.) I gather that obesity research is being hit hard, and some others as well - but any details from people in a position to know would be appreciated.This is a heck of a time to be laid off, that's for sure. Here's hoping that things aren't as bad as I'm hearing. . .Comments (33) + TrackBacks (0) | Category: Business and Markets | Current Events Protein Folding: Complexity to Make More Complexity?Posted by DerekWant a hard problem? Something to really keep you challenged? Try protein folding. That'll eat up all those spare computational cycles you have lounging around and come back to ask for more. And it'll do the same for your brain cells, too, for that matter.The reason is that a protein of any reasonable size has a staggering number of shapes it can adopt. If you hold a ball-and-stick model of one, you realize pretty quickly that there are an awful lot of rotatable bonds in there (not least because they flop around while you're trying to hold the model in your hands). My daughter was playing around with a toy once that was made of snap-together parts that looked like elbow macaroni pieces, and I told her that this was just like a lot of molecules inside her body. We folded and twisted the thing around very quickly to a wide variety of shapes, even though it only had ten links or so, and I then pointed out to her that real proteins all had different things sticking off at right angles in the middle of each piece, making the whole situation even crazier.There's a new (open access) paper in PNAS that illustrates some of the difficulties. The authors have been studying man-made proteins that have substantially similar sequences of amino acids, but still have different folding and overall shape. In this latest work, they've made it up to two proteins (56 amino acids each) that have 95% sequence identity, but still have very different folds. It's just a few key residues that make the difference and kick the overall protein into a different energetic and structural landscape. The other regions of the proteins can be mutated pretty substantially without affecting their overall folding, on the other hand. (In the picture, the red residues are the key ones and the blue areas are the identical/can-be-mutated domains). This ties in with an overall theme of biology - it's nonlinear as can be. The systems in it are huge and hugely complicated, but the importance of the various parts varies enormously. There are small key chokepoints in many physiological systems that can't be messed with, just as there are some amino acids that can't be touched in a given protein. (Dramatic examples include the many single-amino-acid based genetic disorders).But perhaps the way to look at it is that the complexity is actually an attempt to overcome this nonlinearity. Otherwise the system would be too brittle to work. All those overlapping, compensating, inter-regulating feedback loops that you find in biochemistry are, I think, a largely successful attempt to run a robust organism out of what are fundamentally not very robust components. Evolution is a tinkerer, most definitely, and there sure is an awful lot of tinkering that's been needed.Comments (8) + TrackBacks (0) | Category: General Scientific News | In Silico September 24, 2008Ariad's Patent: A Court RulesPosted by DerekOver the years on this blog, I’ve written quite a few times about Ariad Pharmaceuticals and their quest to assert some rather sweeping patent rights. For background, see here and search for "Ariad" - there's a lot to read, in you're in the mood. The short version is that the company is the licensee of a patent which was issued with extremely broad claims around the NF-kappaB pathway in cells. Dozens and dozens of claims – the thing just drones on and on about compounds, methods, techniques that affect, inhibit, modulate, fill-in-your-verb anything that regulates, changes, modulates, etc. anything to do with NF-kappaB.My problem with that is I think that claiming such broad swaths of biochemical mechanism is counterproductive. It’s bad for drug research, bad for patent law, and bad for the enterprise of science in general. For example, the company had no compounds to actually enable a lot of these claims when the patent was issued. A lot of other people did, though, because that pathway is tied up with all sorts of cellular processes, especially those dealing with inflammation and immune response. So Ariad immediately went after other companies with profitable drugs whose mechanism of action went, at least partly, through their newfound patent rights. I find it perverse that a company, rather than patenting their drug, could be able to patent the idea of how a yet-to-be-found drug might work, or retroactively, having had no role in the process at all, claim the rights to other drugs that had already been developed and marketed by someone else.Of course, all this ended up in litigation, which has gone on for years now. There are all sorts of issues – you have the separate court cases with Lilly and Amgen, for one, and then there’s the question of whether Ariad’s patent is valid at all. I’ve chronicled some of the twists and turns – Lilly, for example, lost the first round in court (to my, and no doubt their, disbelief).But the latest news is much more to my liking. Here’s the background: Amgen struck first in 2006, fearing a lawsuit by Ariad over the use of Enbrel – hey, it goes through NF-kappaB, so it’s fair game, right? Amgen asked for a declaration that all 203 claims of the Ariad patent were invalid. Ariad wanted that dismissed, naturally. But in September of 2006, the court turned them down, saying that Amgen did indeed have grounds to sue, since internal Ariad presentation documents specifically mentioned targeting Enbrel (and another Amgen product, Kineret) as part of their business strategy. (The court also took a moment to point out that had these documents not turned up, Ariad would have gotten its desired dismissal right there).Ariad followed up by saying that they’d done no work related to whether the Amgen drugs infringed its patent, but they were going to do so now, by gosh, and in April 2007 they added a counterclaim that Amgen had indeed infringed 22 of the claims. (They later revised that down to nine). By January of this year, they’d dropped the Kineret part of the case and cut the list of claims down to seven.But court found, in a summary judgment, that Amgen had indeed not infringed the Ariad patent. The use of Enbrel, they ruled, falls outside the scope of Ariad’s claims – mainly because all of Ariad’s claims related to reducing NF-kappaB activity inside the cell, and Enbrel acts on TNF-alpha exclusively outside the cell and never enters cells at all. Ariad has no case for infringement.But there was another ruling, which I found quite interesting, and want to go into in detail. During this litigation, Amgen had proposed a broad covenant with Ariad not to sue them, and Ariad responded that sure, they’d sign that – but only covering Enbrel and Kineret. They reserved the right to sue at some future date about something else, you see.Amgen rejected this idea, but Ariad went ahead and publicly declared that they’d abide unilaterally by their proposal – and then they turned around and asked the court to butt out of the original Amgen motion to invalidate all 203 claims of their patent, on the grounds that their covenant deprived the court of jurisdiction to consider the request. After all, they said, the only issues here were Enbrel and Kineret, and they’d promised not to sue Amgen over those, anyway! (Now you see why Ariad would go to the trouble of entering into a covenant with, basically, themselves).Amgen didn’t go for that at all, saying that they were trying, once and for all, to settle the issue of whether Ariad could sue them on any ground related to the original patent – neglecting, as far as I can tell, to append the phrase delenda est Cartago to their filing. They disparaged Ariad’s maneuver as a last-ditch attempt to avoid arguing about invalidity and unenforceability, and said that they had no interest in leaving Ariad’s patent issues open and being sued later on at Ariad’s convenience. I’m paraphrasing here from the court documents, but not by very much, I have to tell you. There’s a distinctly irritated tone to most of the filings in this case.The court went for Ariad on part of this, saying that Amgen’s potential pipeline of drugs and Ariad’s possible lawsuits didn’t amount to a real controversy – not compared to the other two products, which after all had been specifically mentioned in Ariad’s internal documents. Amgen’s attempts to go on with its invalidity claims were no longer on the table. But, as the latest document goes on to say, “The court reaches the opposite conclusion with regard to Amgen’s declaratory judgment claim of unenforceability”. The court held that it did indeed have jurisdiction to hear that part of the case.Amgen’s line of argument was inequitable conduct – that when Ariad’s patent was filed, that the parties involved had not met the “candor and good faith” requirement to disclose all known information related to patentability. They claimed this both for the initial filing and for the PTO’s re-examination of the patent, but it’s the latter that was an issue in this latest ruling. Ariad had filed declarations by two expert witnesses, Inder Verma and Thomas Kadesch, during that process. Amgen claims that Verma’s statement is misleading, and that Ariad didn’t point that that he’d published articles that appear to contradict his own statements. And as for Kadesch, he was deposed by Amgen in the course of another trial that they were involved in (vs. Roche), and they claim that he recanted testimony that he’d given for Ariad in the Lilly trial, which was used by Ariad in their dealings with the PTO. (Amgen apparently had to pry the Kadesch’s reversal documents out of Roche with a subpoena).Ariad did finally get around to submitting all these details to the PTO, but only during the course of 2007 and 2008, after the Amgen legal wrangling was underway. And Amgen claims that they dumped most of the really hot stuff in with a pile of other things, so as not to call attention to any of it. As it turns out, the court found that Ariad had behaved properly with respect to the Kadesch documents – but the Verma stuff was another matter. In his statement for Ariad, Verma said several times that the actions of glucocorticoids through NF-kappaB were poorly understood, not known, etc. But his own articles concluded that glucocorticoids repressed NF-kappaB-mediated transcription, making those statements hard to reconcile.If this was indeed evidence of inequitable conduct, the case all turned on the criteria worked out in a previous case (Rohm and Haas) on whether Ariad had voluntarily submitted this later evidence to the PTO. The court found that there was no evidence for that, that Ariad had only disclosed these documents under threat of Amgen’s litigation, and that Amgen’s motion for (partial) summary judgment on equitable conduct was thus granted.So not only does Ariad have a ruling that interprets its claims in a way it doesn't like (and lets Amgen off the hook, besides), it also has one that raises significant concerns about inequitable conduct, and calls the entire enforceability of its patent into question. Not a good day for them - but a good day for common sense.Comments (6) + TrackBacks (0) | Category: Patents and IP September 23, 2008You Call That An X-Ray Source?Posted by DerekOver the years, when some puzzling feature of a drug candidate’s binding to a target came up, I’ve often said “Well, we’re not going to know what’s happening until some lunatic builds a femtosecond X-ray laser”. Various lunatics are now pitching in to build some. I’m going to have to revise my lines.The reason I’d say such a mouthful is that we already, of course, get a lot of structural information from X-ray beams. Shining them through crystals of various substances can, after a good deal of number-crunching in the background, give you a three-dimensional picture of how the unit molecules have packed together. Proteins can be crystallized, too, although it can be something of a black art, and they can be either crystallized with or soaked with our small molecules, giving us a picture of how they’re actually binding.There are, as mentioned earlier around here, plenty of ways for this process to go wrong. For starters, a lot of things – many of them especially interesting – just don’t crystallize. And the crystals themselves may or may not be showing you a structure that’s relevant to the question you’re trying to answer – that’s particularly true in the case of those ligand-bound protein structures. And the whole process is only good for static pictures of things that aren’t moving around. It used to take many days to collect enough data for a good crystal structure. That moved down to hours as X-ray sources got brighter and detectors got better, and now X-ray synchrotrons will blast away at your crystals and give you enough reflections inside of twenty minutes. And that’s great, but molecules move around a trillion times faster than that, so we’re necessarily seeing an average of where they hang out the most.Enter the femtosecond X-ray laser. A laser will put out the cleanest X-ray beam that anyone’s ever seen, a completely coherent one at an exact (and short) wavelength which should give wonderful reflection data. The only ways we know how to do that are on large scale, too, so it’s going to be a relatively bright source as well. The data should come so quickly, in fact, that several things which are now impossible are within reach: X-ray structures of single molecules, for one. X-rays of things that aren’t in a crystalline state at all, for another. And femtosecond-scale sequential X-ray structures – in effect, well-resolved high-speed movies of molecular motions.Now that will be something to see. Getting all that to work is going to be quite a job, not least because X-ray bursts of this sort will probably destroy the sample that they're analyzing. But there are two free-electron X-ray lasers under construction – one set to complete next year at Stanford’s SLAC facility and a larger one that will be built in Hamburg. “Large” is the word here. The smaller SLAC instrument is already two kilometerslong. According to an article in Nature, though, a Japanese group have proposed some ways to make future instruments smaller and more efficient – all the way down, to, um, the size of a couple of football fields. But there’s another completely different technology coming along (laser-plasma wakefield instruments) that could produce far shorter X-rays in one hundredth the space, which is more like it.I don’t think we’re going to see a benchtop-sized X-ray laser any time soon, especially since these things are going to need to be large just to get up to the brightness that will be needed. But I’m very interested to see what even the first generation machine at Stanford will be able to do. There are a lot of mysteries in the way that molecules move and interact, and we may finally be about to get a look at some of them.Comments (12) + TrackBacks (0) | Category: Analytical Chemistry September 22, 2008More Than ThisPosted by DerekScience is taking a look at the 1991 members of Yale’s Molecular Biology and Biophysics PhD program. The ostensible focus of the article is to see what the effect of flat federal research funding has been on young potential faculty members, but there’s a lot more to pick up on than that.The first thing to note is that out of 26 PhDs from that year’s class, only one of them currently has a tenured position in academia. Five others are doing science in some sort of academic setting, but only one of those is tenure-track. And you can tell that for at least a few observers, the response to those numbers is “What went wrong?”Well, nothing did. As it turned out, the students didn’t necessarily come out of the program on a mission to go out and get tenure. But there was no particular way to blame the research funding environment for the numbers, because almost no one that Science interviewed mentioned that as a factor at all. Instead, many of them decided that there might be something more (or at least something else) to life than going from being a grad student and post-doc directly to. . .supervising more grad students and post-docs: For some MB&Bers, academia was never really an option. "Even as an undergraduate in college, I never bought into the concept of being a professor," says Deborah Kinch, associate director for regulatory affairs at Biogen Idec in Cambridge. "Being a grad student is the last bastion of indentured servitude, and being a faculty member is pretty much the same thing, at least until you get tenure. Earning the same low salary and fighting for every grant--that was the last thing I wanted to do. . .. . . Midway through their graduate training, a few MB&Bers hatched the idea of a seminar series to hear from former graduates working outside the academic fold. (Athena) Nagi said the group wrestled with the definition of an alternative career and decided that the answer was, in essence, "anything that didn't involve teaching at a major research university”. . .what (Tammy) Spain remembers most were their reasons for branching out. "They all said they didn't want to go into academia. None of them said, 'I failed.' None had even tried to find an academic job. It was the first time I got the sense that there was no shame in not going into academia."That heightened sense of empowerment reinforced what some class members were already feeling. "At first, you think that academia makes sense," says Nagi. "But by your 3rd or 4th year, you start to get the lay of the land and look at the options. You realize that a postdoc isn't just for 1 year and that there are multiple postdocs."I particularly like the way that a third-year graduate student had never realized until then that there was no shame in not going into academia. This is a major problem in academic science – the amount of this attitude varies from department to department, but there’s always some of it floating around. It’s no wonder that some of these people were baffled by the prospect of what they were going to do with their lives, because a large, important range of choices was being minimized or ignored.But I have no room to talk – by that point in my graduate career, I wasn’t clear about what I was going to do, either. I was getting pretty sure, though, that going off and fighting for tenure at a major university was not in the running. I’d seen what the younger faculty put up with in my department, and it didn’t look much better than the life I was leading as a grad student. In many ways, actually, it was worse. Why would I want to do that?As it turns out, a good number of the 1991 Yale people ended up at various small biotech companies. Some of them have made a success of it, and naturally enough, some of them are out of science altogether. But the rarest, least likely thing for them to do was to get tenure – or even to try. When I think back on the folks I went to grad school with in the mid-1980s, the picture is very similar. You just wish that there were a way to make this sorting-out process less painful. . .Comments (50) + TrackBacks (0) | Category: Academia (vs. Industry) | Graduate School September 19, 2008Sunesis: No Substitutions Allowed?Posted by DerekA colleague mentioned to me the other day that Sunesis Pharmaceuticals had let many of its remaining research staff go back during the summer – they’re battening down to try to get their main clinical candidate through for leukemia and ovarian cancer. That’s a common phase of life for a small company trying to go it alone. Clinical trials are expensive, and so are scientists, and sometimes a company finds that it can’t afford both at the same time. Amylin, to pick one example, went through so many cycles of that (starting in the mid-1990s) that I completely lost count.The Sunesis news struck me, though, because if you go back a few years in the literature, they’re all over the place. The company was aggressively investigating (and promoting) a technique called “tethering” as a platform for drug discovery. Back around 2003, they were all over the journals with it.Tethering was one of those neat ideas which seems to have been a lot of work to reduce to practice. It’s a variation, in its way, of another one of those techniques called Dynamic Combinatorial Chemistry. In DCC, you take a good-sized collection of compounds which can form reversible bonds with each other. Thiols (R-SH) have been used a lot, since they can form disulfides (R-SS-R), which can easily come apart and re-form with other thiols. In the presence of some target or template, such as the binding site of a protein, the idea is that any disulfide combination that manages to bind well will get enhanced in the final mixture, since it spends more time out of the swim of potential reactants. Comparing the product distribution with and without the target protein can point you to a potential lead structure to optimize. (You can also turn it around and make synthetic receptors (PDF) for molecules that you're interested in).The idea behind tethering was, at least in one of its main variations, to introduce an extra thiol group into a target protein somewhere close to its active site. Then this mutant protein would be screening against a library of small molecules with thiol groups of their own, with the idea that if there was a binding site near that thiol that it would be found by preferential disulfide formation between it and some member of the screening library. Then came the second step. Normal, unmutated protein would be exposed to a mix of that preferred thiol and a library of other potential thiol coupling partners, in an attempt to find another preferred extension into the binding cavity. So this was basically a way to do DCC, but giving it a leg up by trying to make sure that there was a good amount of at least one thing that could bind to some relevant part of the target.That tells you that standard from-the-ground-up DCC must have some difficulties, since if it worked as well as its concept you wouldn’t need to put your thumb on the scales like that. But I was never sure how well tethering worked, either. The company published numerous examples of it, but I don’t know if any of these compounds ever got anywhere (and indeed, I’m not at all sure that their current clinical candidate was discovered by this technique). There are several places where things could break down. Making a mutant protein introduces some uncertainty, for starters. That SH group might not change things, or it might change them just enough so that the binding site you find doesn’t quite exist when you switch to the wild type. And any binding site you find in the first round isn’t necessarily a productive one – the original protein SH group was targeted to try to dangle out over the right part of the protein, but there are no guarantees about that. Past that, even if you get through the second round and find some new disulfide hits (no sure thing), they are, well. . .they’re disulfides. And those are poor bets for drugs.That’s where the real weak point of DCC is in general, to my mind. Using reversible reactions gives you compounds with too much potential to fall apart, so the first thing you have to do is replace those bonds with something sturdier – and that’s not always easy, or even possible. There are very, very few clean substitutions available in the chemical world. Nothing’s quite like a nitrile except a nitrile, and there’s only one thing shaped exactly like a t-butyl group: another t-butyl. Likewise, the only thing that’s guaranteed to look and act like a disulfide is a disulfide. A two or three carbon chain replacement is the logical place to start, but that might be synthetically tricky, or (even more often) might turn out to be a completely different sort of compound once you’ve made it.In the end, I think tethering turned out to be an excellent means to get some very interesting papers published in some good journals. (The publications have continued to this day). But beyond that, I’m not so sure. I’d be glad to hear from any ex-Sunesis people with other views. . .Comments (23) + TrackBacks (0) | Category: Cancer | Drug Industry History September 17, 2008Sugars: Still Crazy After All These YearsPosted by DerekI did carbohydrate chemistry for my PhD - well, I used carbohydrates as starting materials to make other molecules, but I did my share of pure carbohydrate stuff along the way. And although that was over twenty years ago, the stuff I did is still considered by most people to be a sort of esoteric thing, an odd specialty that not many people have experience with. Time has clearly not mainstreamed sugar chemistry.It's not like people don't use the things, often for just the reasons that I used to (as versatile chiral starting materials). But the reputation of the compounds lingers. I think it's because of all the odd little reactions that sugars do. There's a certain amount of knowledge that has to be learned - all that stuff with the anomeric center, for starters, and all the name reactions that only occur in sugars, like the Ferrier rearrangement.Then there are the protecting groups. With all those hydroxys hanging around, a lot of them are going to have to be tied up for extended periods while your work gets done. But every hydroxy group on a sugar ring has a slightly different personality - they acylate and deacylate in a particular order, for one thing, which varies from one sugar system to another. And there are the acetals and ketals to tie up two hydroxyls at once - very useful, but there are a lot of different combinations that can form under different conditions and with different carbonyl reactants.The closest analog to the field that I can think of is steroid chemistry. In its day, that was a hugely popular and important field, with all sorts of ins and outs - tricky transformations that you learned from the old hands. But these days, hardly anyone cares - pure steroid chemistry is a backwater, and many of the esoteric reactions are largely forgotten. Sugar chemistry has escaped that fate - it's still relevant - but hasn't escaped the atmosphere of an eccentric club.My own sugar knowledge, while still sound, is not exactly up to date. I know that the field has moved on over the years, but I've had only sporadic need to keep up, since carbohydrates don't appear in many drug structures. I've been able to work in some of them once in a while, but I've never worked on a project where my sugar experience has been front and center.Comments (13) + TrackBacks (0) | Category: Life in the Drug Labs Ranbaxy: Cutting Corners, or Falsely Accused?Posted by DerekWhile the US has the world's most expensive prescription drugs, we have the world's cheapest generics: once that patent goes away, it goes away. But the generic drug business is still very profitable, and it's viciously competitive. One of the biggest players is India's Ranbaxy, now in the process of being acquired by Japan's Daiichi Sankyo. They compete hard at every step of the process, from fighting patent cases in order to make drugs go generic more quickly, right down to price and distribution to pharmacies..But it looks like they've been pushing it a bit too hard. The FDA has banned the import of thirty Ranbaxy-made drug substances after uncovering what they say are bad practices at three of the company's plants in India. And this comes on top of another investigation, an even more serious one, looking into whether the company out-and-out falsified data during the drug approval process.The company seems to be co-operating with the first investigation, but they're fighting back hard on the second one - which makes sense, because that's the one that can really get them in trouble. Ranbaxy, for its part, seems to have suggested that some big-pharma rivals are behind the accusation. I doubt that myself, although it's not impossible - but neither is it impossible that the charges have something behind them. US companies have found themselves in big trouble over such issues, too.Overall, what Ranbaxy and the other Indian drugmakers have to fear is ending up in the same public opinion category as the Chinese companies, who have had one quality scandal after another. It's going to be a long time before they lose their bad reputation, and the Indian firms definitely don't need to throw away what they've built up. Look for Ranbaxy to try to clear its name as fast and as publicly as possible.Comments (20) + TrackBacks (0) | Category: Business and Markets September 16, 2008Neil Bartlett, 1932-2008Posted by DerekI’ve neglected to note the death of Neil Bartlett, famous for showing that the noble gases would in fact form chemical bonds. This work was a real triumph, since the great majority of scientific opinion at the time was that such compounds were impossible. Bartlett, though, formed a rather startling compound while working on the platinum fluorides, which he realized was actually a salt of dioxygen. The idea that oxygen would be oxidized to a cation in an isolable salt was weird enough at the time, and Bartlett realized that if this could happen, then the same system should be able to oxidize xenon.And so it did. It’s difficult to convey how much nerve it takes to do experiments like this. I don’t mean the dangers of working with such reactive fluorine compounds, although that’s certainly not to be ignored. (Bartlett spent much of his career working in this area, and only a skilled experimentalist could do that and remain in one piece). No, it’s actually very hard to get out there on the edge of what’s known and do things as crazy as making salts of oxygen and fluorides of noble gases, Consider that if you’d lined up a hundred high-ranking chemists to vet these experiments beforehand, most of them would have pursed their lips and said “Are you sure that you’re not just wasting your time on this stuff?” It takes nerve, and not everyone has it – but Bartlett did, and he had the brains and the skills to go along with it. You need all three.There’s a good appreciation of him in Nature, which points out – to my mind, absolutely correctly – that he should have won the Nobel Prize for this work. In fact, I thought he had for a long time, and only a few years ago realized that I had that wrong. (I may have been reinforced in my opinion by a statement in Primo Levi’s The Periodic Table ). I think that if you polled chemists as a group, you’d find that a majority would be under the same impression – and if that’s not a sign of the highest-level work, having everyone surprised that you never got a Nobel, then I don’t know what is.Comments (5) + TrackBacks (0) | Category: Inorganic Chemistry | Who Discovers and Why September 15, 2008Extracting Money From Matthias Rath, For A ChangePosted by DerekI need some cheering up this morning – one of my favorite writers, David Foster Wallace, has died most unexpectedly. Perhaps, in looking back over his best work, it wasn’t as unexpected as all that, but you still never see these things coming.So I’m glad to report, by contrast, that Dr. Matthias Rath has some problems of his own. Rath, some of you may recall, is one of those people who usually has “controversial” somewhere in front of his name in news articles. I’ve never thought of him that way myself: he’s always seemed just a particularly brazen and heartless con artist. He’s made large sums of money by telling HIV-infected patients that antiretroviral drugs are killing them, and that they should instead cure themselves with vitamin supplements purchased from, yes, Dr. Rath. His rants about the pharmaceutical industry are contemptible – Rath claims, naturally, that we’re a gang of evil poisoners, which is at least a field that he knows something about. He’s one of those people that you’re ashamed to share DNA homology with.To be scrupulously fair, Rath appears to have distributed his supplements for free to the poorest patients in places like South Africa, which has surely brought down his average profit-per-suffering-death. But he’s been happy to tell wealthier customers in the US and Europe that he can not only cure HIV infection, but various cancers and other fatal ailments, with no convincing data of any kind to back up such claims.Ben Goldacre, the estimable Bad Science columnist for the Guardian newspaper, ran a column in early 2007 on Rath and his work in South Africa, and followed that up with two more containing disparaging references. Not caring for this sort of publicity, the Dr. Rath Foundation sued for libel. (Goldacre is no stranger to threats of legal action, it seems). I am happy to report that the suit has now been dropped, and that Rath has been ordered to pay legal costs, which are gratifyingly extensive.It now seems that the Dr. Rath Foundation is moving on to the profitable Russian market – with plenty of bad health and plenty of money sloshing around, it would seem a natural feeding ground for a creature of his type. I hope that the Guardian is able to collect its money in short order, and that Ben Goldacre gets a cut.Comments (24) + TrackBacks (0) | Category: Snake Oil September 12, 2008BMS vs. Imclone: Godzilla Exchanges Legal Language With MothraPosted by DerekI haven’t mentioned the attempt by Bristol-Meyers Squibb to buy out Imclone until now, but there’s a nice . The reasons for the move are unsurprising – BMS would like all the revenue from Erbitux, instead of just a share of it, and sees some value coming up in Imclone’s pipeline (such as their development drug candidate IMC-11F8, vide infra). They’ve waiting quite a while, and apparently feel that the time is right – the only question is how much money such a move will cost them.And that’s the question, all right, since Carl Icahn started talking this week about a mysterious preliminary offer from some unnamed other company for significantly more money ($70/share) than BMS is putting up. A lot of investors seem to have expected a sigh, a roll of the eyes, and a reach back into the pocket for more money - IMCL has been trading above the original $60/share offer. But that’s not what they’re getting, at least so far.In a letter, Bristol-Meyers Squibb’s CEO is now reminding Icahn of a few things that you’d think would be obvious. One of them is that their offer is well-supported and requires no due diligence, as opposed to nebulous preliminary figures from companies that no one will name. The next paragraph is even more to the point:As you know, Bristol-Myers holds the exclusive, long-term marketing rights in the United States to ERBITUX® and related compounds, including IMC-11F8. Bristol-Myers has no intention of agreeing to any modifications to these rights. ImClone also should understand that our offer is for the entire company, and any potential restructuring of the company could severely jeopardize ImClone’s value and deprive ImClone’s stockholders of the benefits of our offer.That’s about the size of it, and I think that this message is being delivered in the way that Icahn understands best – right across the top of the head, with some good wrist action. There’s no reason for BMS to give up on their rights to Imclone’s products, except on terms that would make other potential buyers lose interest. Why would they? There is, I should add, quite a dispute between the two companies about who has the rights to that development antibody, IMC-11F8. Imclone has recently been acting as if BMS has no rights to it at all, but as that WSJ link makes clear, two years ago they clearly stated to Merck KGaA that the antibody falls within the scope of the BMS agreement. It's hard for me to see how they'll get out of that, and even if they do, it'll take a lot of expensive wrangling.So, if there really is a company willing to go to $70 a share for Imclone, with revenue still flowing to BMS and plenty of legal uncertainty on top of that, well, this is the time for them to speak up. I’m not sure that there is one, despite what Icahn says, but perhaps he’s hoping for one to materialize. He’s always reckoned Imclone to be worth vast amounts more than people who know anything about oncology think it is, so maybe he sees no problem with those figures. Anyone else live in the same world?Update: Icahn has already replied, in a fashion that makes this affair look to go on a while. He says that he "doesn't understand the point" of the BMS letter, and goes on to say:. . .With respect to a potential restructuring of ImClone, rest assured that we will act in what we consider the best interests of all our shareholders and not just Bristol.Obviously, should you wish to make another offer which you believe we would not find inadequate, you are free to do so. Upon receipt of that offer, we will respond appropriately.Well! My guess is at this point that BMS will sit tight and wait to see if anyone really wants to get in on all this action - betting, reasonably I think, that no one will. I would enjoy it if they raised their bid to, say, $60.25, just to steam up Icahn's windows, but I assume that they're above that. As time goes on, with no competing bids in sight, I would think that Icahn and his board-of-buddies would have to submit the BMS bid to the shareholders - wouldn't they?Comments (3) + TrackBacks (0) | Category: Business and Markets | Cancer September 11, 2008US and UK Biotech: Growth and FormPosted by DerekThere’s an interesting editorial in Nature Biotechnology on a role-playing exercise that took place recently in London. The UK government (in the form of the Bioscience Futures Forum) asked a University of London simulations group to work out what would happen to two identical companies in England and in the US. These would be university spin-offs with promising oncology compounds that had already shown oral activity in tumor models. (Here's the site for the whole effort - I have to say, it looks like an awful lot of effort for a two-day simulation).What happened? Well, things diverged. The US version of the simulated company was able to raise more money, had better access to collaborations with larger companies, and better chances of going public by the end of the simulation. That gave them a broader platform to deal with setbacks in the original compound program. Meanwhile, the UK company faced this:. . . the biotech finance marketplace in the United Kingdom is weak. AIM has little liquidity and virtually no follow-on market. Preemption rights allow existing shareholders to block potentially diluting but opportunistic fundraising rounds, such as private investments in public equity. And there is little access to debt capital for biotech firms.The game also suggests that UK management and investors have mindsets adapted to constrained financial circumstances. They design businesses to fit the financial environment rather than seeking the environment that their business needs. They discount early valuations because of the inflexible later-stage financial circumstances. Their low expectations become self-fulfilling prophecies. In contrast, US management looks to build a sustainable business from the outset, and investors get higher returns as a consequence.What I found interesting about the editorial, though, wasn’t these conclusions per se – after all, as the piece goes on to say, they aren’t really a surprise. (That makes you wonder even more about the time and money that went into this, but that's another issue). No, the surprise was the recommendation at the end: while the government agency that ran this study is suggesting tax changes, entrepreneur training, various investment initiatives, and so on, the Nature Biotechnology writers ask whether it might not be simpler just to send promising UK ideas to America. Do the science in Great Britain, they say, and spin off your discovery in the US, where they know how to fund these things. You'll benefit patients faster, for sure.They’re probably right about that, although it’s not something that the UK government is going to endorse. (After all, that means that the resulting jobs will be created in the US, too). But that illustrates something I’ve said here before, about how far ahead the VC and start-up infrastructure is here in America. There’s no other place in the world that does a better job of funding wild ideas and giving them a chance to succeed in the market. The startup culture here a vital part of the economy and a great benefit for the world, and we should make sure to keep it as healthy as we can.Comments (13) + TrackBacks (0) | Category: Business and Markets | Who Discovers and Why September 10, 2008Pfizer / Bayer?Posted by DerekThe rumor seems to be going around that Pfizer might be making a bid for Bayer (aka Bayer/Schering). That sounds ridiculous to me, and if Pfizer actually does such a thing, then its management is even more starved for ideas than its nastiest critics could believe.Why all the negativity? Well, Bayer doesn’t seem to be much of a fit, for one thing. The company’s Nexavar (sorafenib) oncology drug competes directly head-to-head with Pfizer’s Sutent (sunitinib), and a good chunk of that revenue goes to Onyx, anyway. (Which reminds me – I keep seeing mentions of that drug being an Onyx discovery which was picked up by Bayer, which isn’t right. That one was made at Bayer – why Onyx has a piece of it has to do with the biology, not the drug discovery). The market for kidney cancer would be completely tied up by a Pfizer/Bayer deal, which makes you wonder if the resulting behemoth would be required to divest one of the drugs.Pfizer does like to pick up big-selling compounds by buying the whole company behind them, but Bayer/Schering doesn’t have anything in the Lipitor / Celebrex class right now. (Remember Celebrex?) They might have one coming, though, with their Factor Xa inhibitor, rivaroxaban: it’s expected to do very well in the extremely lucrative clotting market, but it’s not there yet. And besides, some of that one is already tied up with J&J, at least in the U.S.Then there’s the general objection: I’d argue that Pfizer is in the shape it’s in because they’ve pursued the big, big, acquisition strategy. Their own labs have been unproductive, and they unfortunately seem to spray down the research organizations they purchase with whatever’s in the air supply at the home base. OK, that’s probably unfair – but no one can deny that as a whole, Pfizer’s internal drug discovery efforts have been remarkably frustrating for many years now. And they’ve got a massive cost structure, what with all the various facilities they’ve accumulated over the years, which is what’s led to things like their mass exodus from Michigan.More of that sort of thing is what I expect from Pfizer, not some big acquisition. (And I suppose that it should be mentioned that it’s now a widely held belief that more layoffs are coming there this fall, anyway). But if they buy something, it won’t be pretty. What they need is revenue to replace Lipitor in a few years, not people or research facilities. And that’s another reason that a Bayer purchase makes no sense – have you looked into how hard it is to lay people off or close a site in Germany? Years, it takes years, and buckets of money – just what Pfizer doesn’t need to take on.So if you need an excuse to dump Pfizer’s stock (and why, exactly, would you be holding Pfizer stock?) a purchase of Bayer would be the perfect signal that they’ve lost their minds in Groton. I don’t think they have, though. Not completely. Not quite yet.Comments (30) + TrackBacks (0) | Category: Business and Markets September 9, 2008Antipsychotics: Do They Work For A Completely Different Reason?Posted by DerekAs I’ve noted here, and many others have elsewhere, we have very little idea how many important central nervous system drugs actually work. Antidepressants, antipsychotics, antiseizure medications for epilepsy – the real workings of these drugs are quite obscure. The standard explanation for this state of things is that the human brain is extremely complicated and difficult to study, and that’s absolutely right.But there’s an interesting paper on antipsychotics that’s just come out from a group at Duke, suggesting that there’s an important common mechanism that has been missed up until now. One thing that everyone can agree on is that dopamine receptors are important in this area. Which ones, and how they should be affected (agonist, antagonist, inverse partial what-have-you) – now that’s a subject for argument, but I don’t think you’ll find anyone who says that the dopaminergic system isn’t a big factor. Helping to keep the argument going is the fact that the existing drugs have a rather wide spectrum of activity against the main dopamine receptors.But for some years now, the D2 subtype has been considered first among equals in this area. Binding affinity to D2 correlates as well as anything does to clinical efficacy, but when you look closer, the various drugs have different profiles as inverse agonists and antagonists of the receptor. What this latest study shows, though, is that a completely different signaling pathway – other than the classic GPCR signaling one – might well be involved. A protein called beta-arrestin has long been known to be important in receptor trafficking – movement of the receptor protein to and from the cell surface. A few years ago, it was shown that beta-arrestin isn’t just some sort of cellular tugboat in these systems, but can participate in another signaling pathway entirely.Dopamine receptors were already complicated when I worked on them, but they’ve gotten a lot hairier since then. The beta-arrestin work makes things even trickier: who would have thought that these GPCRs, with all of their well-established and subtle signaling modes, also participated in a totally different signaling network at the same time? It’s like finding out that all your hammers can also drive screws, using some gizmo hidden in their handles that you didn’t even know was there.When this latest team looked at the various clinical antipsychotics, what they found was that no matter what their profile in the traditional D2 signaling assays, they all are very good at disrupting the D2/beta-arrestin pathway. Since some of the downstream targets in that pathway (a protein called Akt and a kinase, GSK-3) have already been associated with schizophrenia, this may well be a big factor behind antipsychotic efficacy, and one that no one in the drug discovery business has paid much attention to. As soon as someone gets this formatted for a high-throughput assay, though, that will change – and it could lead to entirely new compound classes in this area. Of course, there’s still a lot that we don’t know. What, for example, does beta-arrestin signaling actually do in schizophrenia? Akt and GSK-3 are powerful signaling players, involved in all sorts of pathways. Untangling their roles, or the roles of other yet-unknown beta-arrestin driven processes, will keep the biologists busy for a good long while. And the existing antipsychotics hit quite a few other receptors as well – what’s the role of the beta-arrestin system in those interactions? The brain will keep us busy for a good long while, and so will the signaling receptors.Comments (5) + TrackBacks (0) | Category: Biological News | The Central Nervous System September 8, 2008The Complicated Causes of CancerPosted by DerekSince I was just banging on the table (or the lab bench) the other day about how many diseases aren’t single-factor, and about how many diseases (like cancer) aren’t even single diseases, I thought this would be a good time to haul out some evidence for that. The data are here thanks to some recent papers by groups who are sequencing various tumor lines, looking for common mutations as new drug targets. (The Cancer Genome Atlas, an NIH project, is behind a lot of work in this area).But what’s become clear, if it wasn’t already, is that various cancer lines have a startlingly wide array of mutations. Recent work from Bert Vogelstein’s group at Johns Hopkins (with a host of collaborators) and from the CGA itself now show that there are an average of 63 mutations in pancreatic cancer cells, and 47 in glioblastomas, two of the nastiest tumors around. The first impulse might be to think “Great! Plenty of drug targets to go around!”But hold on. For one thing, even though these mutations are surely not all equal, the fact that there are so many makes you wonder about whether attacking any one of them alone can make much of a difference. And different patients can have varying suites of those mutations, so it’s difficult to imagine that going after just one or two of those targets will be enough to treat a majority of cases. This work follows up on earlier studies in other tumor lines, all of which seem to point in the same direction: patients who are currently classed as having the same type of cancer really don’t.This won’t come as a surprise to most oncologists, who have seen for themselves the widely varying responses to current therapies. The challenge is to figure out what these various changes mean, and how to classify patients to give them the best therapy. It’s not going to be easy. Just doing the math on the possible interactions of several dozen mutations with a list of possible treatment regimes is enough to make you pause. The hope is that most patients will fall into broad categories, which will line up, more or less, with broad categories of treatment. But it’s not going to be a good fit, most likely, and even getting those approximations to work is taking a lot of time and effort. (Just think back about how long you’ve been hearing about the wonderful new age of personalized medicine. . .)We're not going to be able to do this, either, without a second (and much harder) stage of research: figuring out why these various mutations are important. Some of them seem to make reasonable sense, but it's not at all clear what a lot of them are doing, especially in concert with each other. There's an awful lot of ditch-digging work out there waiting to be done. For now, the quotes from Vogelstein in a Nature News summary can’t be improved on, though. This is the current state of the art, and it’s up to us to improve on it: "It is apparent from studies like ours that it is going to be even more difficult than expected to derive real cures. . . It is extremely unlikely that drugs that target a single gene, such as Gleevec, will be active against a major fraction of solid tumours”Comments (22) + TrackBacks (0) | Category: Cancer | Drug Development September 5, 2008Samurai! Unleash Your Drug Candidates!Posted by DerekToday’s ration of scientific confusion comes courtesy of Wired, in an article that talks about using a modified form of TMV (tobacco mosaic virus) for delivering silencing RNAs. A group at Maryland has used the virus to deliver various siRNAs to cell lines in vitro, which is an interesting idea. But then it gets the Wired treatment: The short, double-stranded RNA molecules known as siRNA can program cells to destroy disease-causing proteins. Their molecules turn on a cell's own built-in disease-fighting mechanisms. They can be programmed for a wide range of ailments -- from cancers to viruses -- and because they use the cell's own defense mechanisms, they produce minimal side effects.In addition to treating cancers and genetic disorders, siRNA could prove useful against a variety of rare diseases that have, and always will be, overlooked by big pharmaceutical companies -- the long tail of disease.People suffering from similar, exotic maladies could band together and recruit a small team of scientists, as if they were the Seven Samurai, to champion their cause and quickly design a cure.Let’s unravel some of that yarn. What siRNA does, actually, is cause proteins not to be produced, rather than “program cells” to destroy them. The effect lasts for as long as the siRNA is present, so I wouldn’t use the analogy to programming. And it’s true that siRNAs can “turn on a cell’s own built-in disease-fighting mechanisms”, but that’s mostly considered an undesired off-target side effect, which people are still trying to get a handle on. You don’t want to set off immune responses to your RNA therapies, believe me.And in the next sentence, we get to hear more about programming. But what’s glossed over is that we don’t know how to “program” siRNAs for a wide range of ailments yet, because in most cases we don’t know what causes a wide range of ailments to start with. If you don’t know what protein you want to knock down, you’re not going to get very far with siRNA. And what about the diseases that aren’t caused by single proteins (which is most of them?) Putting cancer in a list like that is a sure sign that the author is either exaggerating or doesn’t understand what’s going on, because cancer is not a disease. It’s several thousand diseases, each of which may need to be addressed differently if we’re going to use the word “cure”. The next paragraph works in the “long tail” concept, another hook for the intended audience. But look, for example, at something like Gaucher’s disease, which you’d think was pretty far down that tail. Genzyme is doing tremendous business there, because they actually have something – basically the only thing - that helps. For many of these obscure conditions, it’s not so much that we in the drug industry don’t do anything, it’s that we don’t know what to do. And if we’re going to work on something that we’re not sure we can treat or not, which is the usual situation, we’d rather take our chances on something more potentially lucrative.And that last line, with the Kurosawa reference, is just great. Programming, long-tail, classic foreign movies – this piece must have gone through the editorial process at Wired in about ten minutes. I’ll bet my readers in the drug industry are wondering how they can get together in small teams, whip out their samurai swords, and quickly design cures – admit, you are, aren’t you? Well, the next paragraph of the piece quotes Stephen Hyde of Oxford:” “The speed with which you develop siRNA drugs is truly amazing,” said Stephen Hyde. “In the past, a traditional small molecule drug might take several years of intensive research effort by a large team of scientists to develop. Today, with siRNA technology, it is possible for a single researcher to develop a drug candidate in a few weeks.”It’s hard to know which end of that statement to untangle first. If you know exactly which protein you want to target for a disease, then yes, you can then know what sort of siRNA sequence you want to try to knock it down. But is that a drug, as the first line suggests? Nowhere near. Sad to say, you still have those years and years of clinical testing for safety and efficacy to go through.Now, where Prof. Hyde’s statement makes some sense is in the preclinical world. It does take longer for a team of chemists and biologists to come up with a small-molecule drug candidate, and that’s where the promises of siRNA (and antisense DNA) come in. If you’re targeting the expression of a particular protein (a big if, as I’ve said), then you immediately have a relatively short list of sequences to try, as opposed to the wide-open world of small molecule screening. Chemistry really is only one way to get to a drug candidate, and just because it’s been the way for most drugs until now doesn’t mean it always will be.But it’s not going to go away, either. Small molecules can do things that changes in protein expression can’t – we can make agonists and antagonists of receptors, for one thing, and we can make inhibitors with varying selectivities across related targets. And there will always be diseases – the majority of diseases – where several things will have to be affected at the same time for any kind of cure to be realized. We’re going to need all the modes of attack we can get.The rest of the Wired article, to its credit, does mention the single biggest problem with siRNAs: their delivery in vivo. And if you get down to the last few sentences, you can find out that the TMV delivery system has not yet been shown to work in a living animal, could cause immune responses even when it does, and has (as yet) no way to target its delivery to a specific cell population. It is, in other words, an ingenious idea – one of many – that has a long way to go before it sees a sick patient. And we have a long way to go before we have seven-scientist samurai teams cranking out cures in a few weeks. Perhaps we’ll live long enough to see it.Comments (9) + TrackBacks (0) | Category: Drug Development | Press Coverage September 4, 2008X-Ray Structures: Handle With CarePosted by DerekX-ray crystallography is wonderful stuff – I think you’ll get chemists to generally agree on that. There’s no other technique that can provide such certainty about the structure of a compound – and for medicinal chemists, it has the invaluable ability to show you a snapshot of your drug candidate bound to its protein target. Of course, not all proteins can be crystallized, and not all of them can be crystallized with drug ligands in them. But an X-ray structure is usually considered the last word, when you can get one – and thanks to automation, computing power, and to brighter X-ray sources, we get more of them than ever.But there are a surprising number of ways that X-ray data can mislead you. For an excellent treatment of these, complete with plenty of references to the recent literature, see an excellent paper coming out in Drug Discovery Today from researchers at Astra-Zeneca (Andy Davis and Stephen St.-Gallay) and Uppsala University (Gerard Kleywegt). These folks all know their computational and structural biology, and they’re willing to tell you how much they don’t know, either.For starters, a small (but significant) number of protein structures derived from X-ray data are just plain wrong. Medicinal chemists should always look first at the resolution of an X-ray structure, since the tighter the data, the better the chance there is of things being as they seem. The authors make the important point that there’s some subjective judgment involved on the part of a crystallographer interpreting raw electron-density maps, and the poorer the resolution, the more judgment calls there are to be made:Nevertheless, most chemists who undertake structure-based design treat a protein crystal structure reverently as if it was determined at very high resolution, regardless of the resolution at which the structure was actually determined (admittedly, crystallographers themselves are not immune to this practice either). Also, the fact that the crystallographer is bound to have made certain assumptions, to have had certain biases and perhaps even to have made mistakes is usually ignored. Assumptions, biases, ambiguities and mistakes may manifest themselves (even in high-resolution structures) at the level of individual atoms, of residues (e.g. sidechain conformations) and beyond. Then there’s the problem of interpreting how your drug candidate interacts with the protein. The ability to get an X-ray structure doesn’t always correlate well with the binding potency of a given compound, so it’s not like you can necessarily count on a lot of clear signals about why the compound is binding. Hydrogen bonds may be perfectly obvious, or they can be rather hard to interpret. Binding through (or through displacement of) water molecules is extremely important, too, and that can be hard to get a handle on as well.And not least, there’s the assumption that your structure is going to do you good once you’ve got it nailed down:It is usually tacitly assumed that the conditions under which the complex was crystallised are relevant, that the observed protein conformation is relevant for interaction with the ligand (i.e. no flexibility in the active-site residues) and that the structure actually contributes insights that will lead to the design of better compounds. While these assumptions seem perfectly reasonable at first sight, they are not all necessarily true. . .That’s a key point, because that’s the sort of error that can really lead you into trouble. After all, everyt | |
