About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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September 28, 2012

EMBL Chemical Biology: Progress in Oncology

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Posted by Derek

This evening's EMBL speaker is Paul Workman on new cancer targets and drug development. He's pointed out that treating cancer (and classifying cancer) by where it's located in the body is actually fairly primitive. Tumor cells in, say, breast cancer surely have more in common with various other type of tumor cells than they do with the normal cells surrounding them.

He claims that we're starting to see attrition rates come down in oncology, and I hope he's right. I see, though, that he's reified the "Valley of Death", which I'm not so sure about. There surely are some ideas in academia that should be moved along to development, but not all of them are worthy. (That's no slur - not all the targets inside the drug companies are worthy either, believe me). I worry that constant referral to a Valley of Death makes it sound as if there's something mysterious going on, when it really doesn't seem that strange to me. This Valley is mostly a gap between what works and what doesn't, rather than between academia and industry.

He also has a good slide on probe compounds versus drugs (here are the details). Probes, he says, need to meet even more stringent criteria for selectivity and potency than drugs do if their purpose is going to be to uncover new biology. Selectivity is usually the hardest barrier. That said, probes have to evolve. You don't find compounds like this right out of an HTS screen, and they're going to need some cycles of med-chem before they're truly ready for use. A less-than-optimal probe shouldn't be seen as a failure, but as an intermediate step.

Comments (7) + TrackBacks (0) | Category: Chemical Biology

Pfizer's New Leaf

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Posted by Derek

Here's a piece by an industry consultant who's interacted with Pfizer a lot over the years. He says that they're really, truly going to change:

But buying companies, partners, and products never added up to a net gain in R&D productivity because the resulting behemoth lacked the key ingredient: integration. Like the industry in general, Pfizer’s acquisitions bought it little else but time. When its enormous R&D engine broke down after failing to produce an adequate pipeline, the company reflexively slashed research spending and staff. But something else happened along the way — a sea change for the company not only in organization but also in philosophy. Like China or the former Soviet Union renouncing past Maoist or Stalinist practices, Pfizer has now declared an end to its legendary imperialism in favor of a new, open and collaborative research model.

Let's just say, that as with many large companies, "open" and "collaborative" have not necessarily been the first words one associates with Pfizer's research strategy. My initial impulse is to discount this stuff as they-have-to-say-that pronouncements from the executive suite. But I'm a cynical person sometimes. If Pfizer really is going to change, theway to convince people (such as their potential collaborators) will be through deeds rather than words. We'll see.

Comments (34) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

Elan's Discovery Efforts - What's Going On?

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Posted by Derek

Elan announced not long ago that they were going to spin off their drug discovery efforts into a separate entity, Neotope. But I've also heard that they've recently let go a large number of people in their discovery effort, and I haven't heard any talk of them being Neotoped - does anyone know what's going on over there?

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

EMBL Chemical Biology: The ChEMBL Database

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John Overington from the EMBL is talking about the ChEMBL database, which is an impressive collection. One thing that I appreciate is that he's being upfront about the error rates in the data. He takes the reports of trouble seriously, but feels (overall) that considering the amount of data they have, and the amount of annotation associated with it, that they've done well.

There are an awful lot of ways that you can work the numbers from their web site, which is both good and bad. If you know what you're doing, you can get some very interesting and potentially useful results, but if you don't, you can mislead yourself more quickly and thoroughly than you ever could by hand. That's common to all powerful tools, naturally.

My talk is right after the next speaker, so I won't be posting for a bit. And no, I will not be writing a critique of my own talk while I'm giving it; that would be a Blog Singularity of some sort.

Comments (5) + TrackBacks (0) | Category: Chemical Biology

EMBL Chemical Biology: Polypharmacology

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Posted by Derek

Brian Shoichet is talking about the old days, 1930 to about 1985 or so. He mentions that Sir James Black called it "rational drug design" back then, which must have been a reaction to something that was considered really irrational. But these guys had a lot of advantages, which is what's leading people back to phenotypic screening. (I can see that I'll need to adjust my own presentation later today, because I'm going to be making the same point!)

His talk is mostly on this recent work, which I'll be blogging about separately soon, because there's a lot of drug discovery information in there. He's wondering as well about why polypharmacology is so pervasive - his studies are pointing that out in detail, but relating that to the old-style of drug discovery suggests that this isn't always a bug, but a feature. Hard-core target-based drug discovery is taking a bit a beating around here today, I have to say.

He's also made a very interesting point which looks to be the subject of an upcoming paper: that living systems signal in a number of time domains, and that this is reflected in ligands. You can see cases (like serotonin) where evolution has used the same ligand in a short time-domain case (ion channels) and a longer one (GPCRs). Nuclear receptors and some other classes work on even longer time scales. Some polypharmacology comes from across-time-domain effects.

Comments (6) + TrackBacks (0) | Category:

EMBL Chemical Biology: Substrate Activity Screening

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The day starts off with Jonathan Ellman talking about substrate activity screening, a very interesting technique that builds on optimized artificial enzyme substrates and turns them into inhibitors. He's published a number of papers on this, and it looks like his current efforts are targeting phosphatases. I wish him luck with that; those have been a very tough field to work in. He also seems to be looking at some of the epigenetic enzymes, and I look forward to seeing how that comes out as well.

I asked him a question at the end of his talk, since I couldn't help but notice that many of his SAR compounds rely on hydrophobic interactions to get potency. His phosphatase inhibitors featured things like a ring with two CF3 groups and a bromine, or another aryl with a cyclohexyl on it, all of which are getting pretty greasy. He replied that they have been able to find some enthalpic interactions (particularly when targeting Cathepsin S), but that they have the same problems as everyone else in finding good polar interactions as opposed to getting potency through grease.

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

September 27, 2012

EMBL Chemical Biology: George Whitesides on Ligand Binding

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Posted by Derek

Now the conference day is winding up with a big talk by George Whitesides. He's talking about his thoughts on enzyme function, with reference to his group's work using carbonic anhydrase as a model. He praises its stability ("a ceramic brick") and other characteristics, as you might expect from someone who's published an entire review on its use in biophysical studies.

So what makes compounds bind to enzyme sites? His take on the hydrophobic effect is that he thinks it's due as much (or more) to changes in networks of water molecules, rather than just the release of structured water at the protein-ligand contact. The latter is important, for sure, but not the whole story. "There is no one hydrophobic effect", he says, "there are many hydrophobic effects".

Another quote: "There ain't nothin' like water", and I definitely agree. We're used to water, since it's the most common chemical substance that we deal with in our lives, but water is weird.

And there's a lot we don't know about it still. For example, Whitesides has just pointed out that we have a reasonable understanding of surface tension in the bulk phase - but not at all for molecular-sized holes. This is crucial for understanding ligand behavior. His view of protein-ligand binding, he says, is very water-centric. . .

Comments (9) + TrackBacks (0) | Category: Chemical Biology

EMBL Chemical Biology: Greasy Labels

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Posted by Derek

Just to emphasize how careful you have to be with all these probes and labels, consider what I'm hearing now from Remigiusz Serwa of the Tate group at Imperial College. His group is looking at farnesylation. People have tried making azido-containing substrates, for later "click" fluorescent labeling of proteins that pick up the label, but the azido group turns out to be a loser here. It's too polar in the greasy world of prenyl groups, and things go haywire.

You'd think that switching the click reaction around would be the answer here - make an alkyne group to be picked up by farnesyltransferase and you're in. But the ones that have been tried so far are terrible substrates for the enzymes. He seems to be on the way to solving that problem, but (interestingly) isn't revealing the structure (yet) of his probe. Must be a manuscript on the way - probably with a patent on the way before that?

Comments (0) + TrackBacks (0) | Category: Chemical Biology

EMBL Chemical Biology: How Receptors Really Work

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The latest talk is from Alanna Schepartz of Yale. I had a chance to ride in from the airport with her yesterday, and she gave me a brief preview of her talk, which is on transport of both molecules and information through the plasma membrane of cells. "Some molecules weren't paying attention when Lipinski's rules came down", she says (Lipinski himself was supposed to be here, but had to cancel at the last minute, BTW).

The example here is the EGF receptor. We know a fair amount about the extracellular domain of this protein, and some about the intracellular part. But the "juxtamembrane" portion connecting the two is more of a mystery, although it's clearly crucial for receptor signaling. Her lab has been using a fluorescent marker for particular protein coil structures. What this work seems to show is that different ligands for EGFR (EGF versus TGF-alpha), which are known to produce different downstream signaling, do so through different structures of the protein. Subtle variations of the coiled-coil helical protein on the intracellular face are meaningful and provide yet another way for these receptors to vary their function.

You'd think that there would have to be some such structural difference, since the two "agonists" do act differently. But actually getting a look at it in action is something else again. This is, to me, another example of "treat the protein as a big molecule" thinking. People who do structure-based drug discovery are used to that viewpoint, but not all molecular and cell biologists are. They'll find chemistry infiltrating their worldview, is my prediction. . .

Comments (5) + TrackBacks (0) | Category: Chemical Biology

EMBL Chemical Biology: Unnatural Amino Acid Labels

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Posted by Derek

Now I'm listening to David Tirrell of Cal Tech, talking about his lab's work on labeling proteins with azidohomoalanine (Aha) as a marker. He's done a good job showing that (if you don't go wild) that replacement of methionine with this amino acid doesn't perturb things very much at all, and there's a recent paper showing how well the technique works (when combined with stable isotope labeling) for analyzing mixtures of low-abundance proteins. You can now buy all the reagents you need to do this.

The Aha can be activated by wild-type Met tRNA synthetase (MetRS), but he's also working with weirder amino acids that require a mutant RS enzyme. This is useful for even finer-grained experiments; the example shown is for monitoring host-pathogen interactions. Using a Yersinia species, he's showing all sorts of complex results, most of which fall into the category of "Must be important, but we don't know what they mean yet". The bacteria inject a number of as-yet-uncharacterized proteins into mammalian cells, for example, and without techniques like these, you'd never find them.

They've gone as far as doing this in whole living nematodes - it looks like this has been disclosed at meetings, but there doesn't appear to be a full paper on this yet.

A nice quote from the talk: "We did a computational search, which didn't help us out very much, but the experiment was great". Words to live by!

Comments (3) + TrackBacks (0) | Category: Chemical Biology

EMBL Chemical Biology: Discovering Catalysts

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Posted by Derek

Right now, there's a talk going on from Helma Wennemers of the ETH. She's working on small peptidic catalysts for organic reactions, what one might think of as "mini-enzymes". They're certainly not as wildly effective as real enzymes, but they're a lot easier to find and modify. Here's an example, which has been extended to solid-supported catalysts here. And whenever I see a solid-supported catalyst, I think "Can you use that for flow chemistry?" I was glad to see that they're done just that - I don't think that work has been published yet, but it seems to work pretty well.

Chemistry like this is a good reminder of just how many catalysts remain to be found. I don't see any reason, a priori, for any reaction to be out of bounds for enzymatic-type catalysis. You have functional groups that can participate in some reaction mechanisms (as is the case for the proline nitrogen in the above work), you have stabilization of transition states, you have sheer physical proximity/effective molarity, and probably other effects that people are still arguing about. Eventually we'll get good enough to design such things, but for now, a combination of design and what I might call "enlightened brute force" looks like the way to go. I'd like to see someone pick some reaction types that are not catalyzed enzymatically and apply these techniques to make something we've never seen before. If we could figure out how to get new metallic centers into these this things (imagine an enzymatic palladium catalyst!), we could really do some wild chemistry. Mind you, I'm not the one who would be trying to get that funded.

Comments (3) + TrackBacks (0) | Category: Chemical Biology

EMBL Chemical Biology: Labeling Proteins

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Posted by Derek

Jason Chin of the MRC Molecular Biology lab in the UK has been talking here about protein labeling and genetic code expansion, an overview of the numerous papers his group has been publishing in this area over the last few years.

And he's just made what I think is a very worthwhile point. While talking about labeling proteins with very reactive alkyne-containing amino acids (for fluorescent "click" applications), he said that some people would look at this and say "Why bother - you can already label these things with GFP". But sticking an entire Green Fluorescent Protein onto an existing one is hardly a silent event. If you're going to think about these things the way a chemist would, you need to come in with something as small and unobtrusive as possible. And it also needs to be something that you can localize, which doesn't just mean "I know what protein it's on".

Chemists think - or had better think - at a higher magnification. What exact surface of the protein is this label on? What residues are next to it? What sort of binding pockets might it be interrogating? We need to treat proteins as molecules, and as molecules they have a lot of detail in them.

Comments (6) + TrackBacks (0) | Category: Chemical Biology

September 26, 2012

EMBL Chemical BIology: Natural Product Multiheterocycles

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Posted by Derek

Chris Walsh of Harvard is talking about the trithiazolylpeptide antibiotics and related compounds. If you thought that only we synthetic organic chemists were crazy enough to link three more heterocycles onto a central pyridine, leading to compounds which "have the solubility of sand" (a direct quote from Walsh), then think again. And they weren't even made by palladium-catalyzed couplings! Since we were talking about macrocycles here the other day, it's worth noting that these are also 29-membered rings and the like.

Here's one of them for you, if you haven't seen these beasts before. Who's synthesized it? Funny you should ask. . .

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

EMBL Chemical Biology: Covalent Probes

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Posted by Derek

A short talk from Steven Verhelst of Munich went into detail on some covalent probes for rhomboid proteases. I've been interested for a while about what happens when you run small electrophilic compounds over proteins - do they stick to everything, or can they show selectivity? The canonical paper on this topic is from the Cravatt group, which I'd recommend to anyone who finds this topic worthy. (Update: the Liebler group at Vanderbilt has also published some excellent work in this area, concentrating on Cys modification). Verhelst had one variety of electrophile that was selective in the active site, and another class that inhibited by sticking all over the place. So the answer is probably "Depends on your protein, and on your electrophile. Try it and see".

Comments (6) + TrackBacks (0) | Category: Chemical Biology

EMBL Chemical Biology: Weird Aggregating Compounds

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Posted by Derek

Now I'm listening to Jim Wells (UCSF) talk about (among other things) this work, where they found a compound aggregating and causing activity in their assays. But this one wasn't doing the standard globular gunk that the usual aggregation gives you. Instead, the compound formed nanofibrils - microns long. And the enzyme that the compound showed activity against turns out to bind to the surface of the fribrils. Wells likens the effect to the way that Brussel sprouts grow, and his electron micrograph does indeed look pretty close. The question is, does this mimic something that happens "in real life", or is it a complete artifact? There's a paper in press in JBC going into some of the details. Just goes to show you that compounds are capable of doing things that you'd never have been able to guess.

Comments (6) + TrackBacks (0) | Category: Chemical Biology

EMBL Chemical Biology: Natural Product Leads

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Posted by Derek

I'm listening to Paul Hergenrother (of Illinois) talk about using natural products as starting materials for compound screening libraries. It's a good idea - he takes readily available complex structures and does a range of organic chemistry on each of them, to make non-natural structures that have the complexity and functionality of natural products. I note that he's taken adrenosterone and made azasteroid derivatives (among many others), very similar to what I talked about here. He's also used quinine, gibbererlic acid, and others.

He's taken the collection thus produced and run them through phenotypic cell screens, with what look like interesting preliminary results. The idea is to look for unusual phenotypes and work backwards to new targets from them, so having a pile of unusual compounds is probably a good starting point. Of course, I have a weakness for phenotypic screens in general, and I suspect I'm going to be hearing a lot about them here over the next few days.

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

Those Drag-Over-the-Coals Interviews

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My column this month in Chemistry World is on high-pressure chemical interviews. Is my impression correct, that the good ol' "let's go to the board and draw out reaction mechnisms" sort of interview is slowly leaving the world?

Comments (30) + TrackBacks (0) | Category: How To Get a Pharma Job

Free the Labels

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Posted by Derek

When you talking assays, "label-free" is a magic phrase. The more thingies you have to stick onto your molecules or targets to see them, the less confidence you'll have that you're actually looking at the system the way you really wanted to see it: as if you weren't looking at it at all. And while we're not quite quantum mechanics, the observer effect is very real in molecular and cell biology - too many interesting techniques perturb the system in the process of reading out.

And there are no perfect label-free assays, otherwise we'd all be using them. In vitro, NMR can tell you an awful lot, but it can require an awful lot of work if you want to correlate structural information with binding events. And mass spec is getting ridiculously sensitive, and can be used to detect compound binding. But even when that works, it doesn't give you any structure (or much spatial resolution after a certain point, if that's what you're looking for - say, in cells). SPR is a great technique for getting kinetic information right out of the primary assay (instant off-rates!) But it's not quite label-free, because you have to immobilize something to a chip to make it work. Thermal shift is an interesting assay, too - but it uses up a fair amount of protein, and some proteins are more sensitive to it than others. No structural information there, either.

There are a couple of techniques that I don't have much experience with that sound intriguing. Capillary electrophoresis for binding is one - you look at mobility changes with your protein when something is bound to it, as you'd imagine. It's supposed to be pretty sensitive. And BLI (bio-layer interferometry) reminds me a bit of SPR, in that it uses an immobilized protein. I'm not sure what the advantages/disadvantages of that one are, but I see it turn up in the literature.

The ideal assay? If you could do NMR, with the sensitivity to detect very small amounts of a compound, with spatial resolution well below subcellular. You'd get binding, localization, and structure all in one shot. That's probably not even possible, but I'd love to be wrong about that.

Comments (15) + TrackBacks (0) | Category: Drug Assays

September 25, 2012

CNN's Cure for Cancer

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Posted by Derek

I've been meaning to write something about the M.D. Anderson announcement of "Moon Shot" programs for cancer therapies. Mostly something about how I'm very glad that they're spending a lot of time and money on this, because there are a lot of good people there, but also about how I truly hate the "Moon Shot" analogy for R&D. As has been said for years, decades. . .the Moon landing was a stupendous feat of applied engineering, but few (if any) new principles had to be discovered along the way. Attacking cancer, though, is like trying to engineer a moon landing when you're not sure where the moon is. Or what it's made out of. Or what the various kinds of rocket fuel might be.

And the whole thing was made much, much worse by CNN, who proclaimed "Cure for Cancer Close" as some sort of exclusive scoop. That ridiculous situation is summed up well here. As it turns out, this was a combination of the M.D. Anderson press release and one of those "We could save more people just by applying our existing knowledge more thoroughly" angles. All in all, a really shoddy performance, which I hope had people both at CNN and M. D. Anderson burying their heads in their hands.

Comments (12) + TrackBacks (0) | Category: Cancer | Press Coverage

A Russian Chemist in Jail

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Posted by Derek

There's a bizarre case in Russia involving chemist Olga Zelenina:

Zelenina heads a laboratory at the Penza Agricultural Institute, some 600 kilometres southeast of Moscow, one of the best-equipped chemical-analysis labs in Russia. She is a specialist in the biology of hemp and poppy, and is a sought-after expert in legal cases involving narcotics produced from these plants.

In September 2011, the defence attorneys of Sergey Shilov, a Russian businessman under investigation by the Russian Federal Drug Control Service (FDCS), asked her to provide an expert opinion on the amount of opiates that could possibly be extracted from 42 metric tonnes of food poppy seeds that Shilov had imported from Spain in 2010. . .

. . .On the basis of gas-chromatography and mass-spectrometry measurements of samples analysed in her lab, Zelenina calculated the overall morphine and codeine content in the poppy-seed consignment in question to be 0.00069% and 0.00049%, respectively. In such low concentrations, opiates can only be identified or extracted in well-equipped analytical chemistry labs, she wrote.

“This opinion apparently failed to satisfy the prosecutors,” says Irina Levontina, a linguist at the Russian Language Institute in Moscow, who is frequently heard as an expert in libel and drug lawsuits. “It has become quite common for Russian prosecutors to accuse independent experts if they don’t like their opinions. It can be downright dangerous for experts to appear in court.”

Apparently so. She was arrested in August, for allegedly assisting drug trafficking, and ordered held until October 15, awaiting a still-unspecified trial date. C&E News reports that scientists in Moscow and elsewhere are signing petitions for her release and showing support for her in court hearings. But if the Russian government doesn't like you, what can avail? Perhaps bad publicity can help?

Update:Zelenina has been released from custody, pending her trial. It's a start, but she's still facing all sorts of penalties if convicted.

Comments (17) + TrackBacks (0) | Category: Current Events

Pharmville: Good Grief, This Looks Awful

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Posted by Derek

A reader sent along a link to this, which appears to be a completely serious effort by Boehringer Ingelheim to make a Facebook game about drug discovery. My guess is that whatever it might teach anyone about drug R&D will be outweighed by what it'll teach them (incorrectly) about the amount of effort needed to do it. No remotely realistic game could ever have enough payoffs to keep people interested. We can only handle that sort of thing in real life; one expects more from one's entertainment.

Comments (10) + TrackBacks (0) | Category: Business and Markets

Sanofi Cuts Back in France

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Posted by Derek

Sanofi looks set to announce cutbacks and re-orgs in France:

In addition to Toulouse, research jobs could go in Montpellier, southern France, in addition to Strasbourg, eastern France, as well as Chilly and Vitry-sur-Seine near Paris.

A number of vaccines unit and support jobs could also be slashed as part of the reshuffle.

Chief Executive Chris Viehbacher, a German Canadian who is Sanofi's first non-French top manager, is now focusing on France as part of his drive to boost productivity in research labs company-wide after wielding the axe in other countries.

"The reality is that our research in France hasn't really come up with a new medicine in 20 years and therefore we have to take a much more productive approach to how we do this," he told analysts in July. "It is a reorganization within France. It's not externalizing research to other countries."

The company is regrouping its research operations around the world into regional hubs - such as Boston, where its rare disease unit Genzyme and cancer research labs are based - while shuttering other laboratories.

That's not going to be popular, given France's history of lively labor relations. But everywhere else in the Sanofi world has heard the swish of the ax, so it can't come as that much of a surprise, can it?

Update: well, here's the announcement itself. And maybe this is my first impression, but compared to what's gone on in other Sanofi sites (like Bridgewater), this one comes across like a shower of dandelion fluff. No reduction in the number of sites, no actual layoffs - just 900 positions to phase out, mostly via attrition, over the next two years. The Toulouse site is the only loose end; that one is the subject of a "working group" to figure out what it's going to do, but I see no actual language about closing it.

Comments (8) + TrackBacks (0) | Category: Business and Markets

September 24, 2012

The One-Stop CRO

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Posted by Derek

C&E News has a good article out on the so-called "one-stop shop" contract research organizations in pharma - these are the Covances and WuXis of the world, who can take on all sorts of preclinical (and clinical) jobs for you under one umbrella.

The old debate over one-stop shopping has, however, become more nuanced in the current pharmaceutical industry environment. Service firms and their customers agree that much of the decision making comes down to where to outsource workhorse chemistry and where to outsource frontline science. Sources agree that a market still exists for boutique CROs that focus on one node along the discovery/development continuum. And some drug firms say they are working with more than one full-service vendor, negating the supposed advantage of one-stop shopping.

There's more of this sort of thing around than ever, of course, but the merits of the whole idea are still being debated. There's no questions that these companies can extend the reach of an organization that doesn't have all these specialities itself, but that doesn't mean that you can't mess things up, either.

Not every drug firm is scaling down internal research. Sonia Pawlak, manager of strategic outsourcing in chemical development at Gilead Sciences, says drug companies with fully developed R&D operations will likely not see much advantage in working with a one-stop-shop contractor. . .Geographical proximity to a supplier is important to Gilead, Pawlak adds, questioning whether linking research and manurfacturing assets across different continents saves the customer time.

I'm used to looking at these companies from the buying end. When you consider the whole CRO world from the other direction, though, you see a vision of de-risked pharma. These people are going to get paid, whether the preclinical program works out or not, whether the clinical trials work or not, whether the eventual drug is approved or not. It's a contract business.

But they're also never going to get paid more than what is in that contract - they will share in no windfalls, get pieces of no blockbusters. So eventually, you end up with two halves of the whole drug R&D business: a drug company that does little or no outsourcing (along with the small R&D discovery companies that outsource everything they can) are in the part that takes the big risks and goes for the big victories, while the CROs are the part that takes on (comparatively) no risk in exchange for a smaller guaranteed payout.

Comments (11) + TrackBacks (0) | Category: Drug Development

Conference Travel

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Posted by Derek

I wanted to mention that later this week I'll be in Heidelberg, attending the EMBO Chemical Biology conference (agenda). So anyone in Hesse or Baden-Württemberg who's been trying to track me down in person, well, you're in luck. It'll be the first time I've been back in Heidelberg in nearly 25 years, although I believe one of its main selling points is that it doesn't change too much (!)

Comments (5) + TrackBacks (0) | Category: Blog Housekeeping

September 21, 2012

Transcelerate: What Is It, Exactly?

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Posted by Derek

A list of big pharma companies have announced that they're setting up a joint venture, Trancelerate, to try to address common precompetitive drug development problems. But that covers a broad area, and this collaboration is more narrowly focused:

Members of TransCelerate have identified clinical study execution as the initiative's initial area of focus. Five projects have been selected by the group for funding and development, including: development of a shared user interface for investigator site portals; mutual recognition of study site qualification and training; development of risk-based site monitoring approach and standards; development of clinical data standards; and establishment of a comparator drug supply model.

Now, that paragraph is hard to get through, I have to say. I understand what they're getting at, and these are all worthy objectives, but I think it could be boiled down to saying "We're going to try not to duplicate each other's work so much when we're setting up clinical trials and finding places to run them. They cost so much already that it's silly for us all to spend money doing the same things that have to be done every time." And other than this, details are few. The initiative will be headquartered in Philadelphia, but that seems to be about it so far.

But this it won't get at the fundamental problems in drug research. Our clinical failure rate of around 90% has very little to do with the factors that Transcelerate is addressing - what they're trying to do is make that failure rate less of a financial burden. That's certainly worth taking on, in lieu of figuring out why our drugs crash and burn so often. That one is a much tougher problem, easily proven by the fact that there are billions of dollars waiting to be picked up for even partial solutions to it.

Comments (18) + TrackBacks (0) | Category: Clinical Trials | Drug Development

We Were Ahead of the Crowd

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Posted by Derek

According to the Wall Street Journal, the periodic table is now cool. It's shown up as a design, uh, element in TV shows, on T-shirts, and so on. (The article even gets quotes from Tom Lehrer, who I'm glad to hear is still with us). And Theodore Gray's coffee-table book The Elements
has now sold 650,000 copies (one of them to me - I recommend it). Of course, Gray has the ultimate periodic-table fan item, if you can afford it:

People who lacked patience for a chemistry set can now buy periodic table shower curtains, T-shirts, coffee mugs and even a periodic coffee table. The furniture piece, made of burred oak with samples of inlaid elements, costs $8,550, plus shipping, which gets pricey. For safety reasons, fluorine, chlorine and bromine are forbidden on airplanes, says Max Whitby in London, who produces the table.

I'd add my own, if I had 9 long ones to spend on one of these. Thick-walled ampoules would do the job, although the fluorine would still present a problem (doesn't it always?) But I suppose most of the radioactive ones (except depleted uranium) are still out. Hand-rubbed varnish would probably stop alpha particles, but not much else.

Comments (13) + TrackBacks (0) | Category: Chemical News

September 20, 2012

Roche: Manhattan Instead of Cambridge

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Posted by Derek

When Roche announced that they were moving their remaining East Coast R&D out of Nutley (NJ), I (and others) thought that the Boston area was surely the front-running location. But we were wrong: they're moving to Manhattan. More specifically, it's Murray Hill, near the NYU Medical Center. Cue the speculation about NYC becoming a biotech R&D hub. . .

Comments (27) + TrackBacks (0) | Category: Business and Markets

Various Links Of Stuff

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Posted by Derek

Swamped with all sorts of stuff today - when science marches on, you have to make sure that it's not leaving its bootprints on your back. But I do have some interesting links:

The bluest of blue-sky brain research, funded by Paul Allen. Fascinating stuff, on several levels - here's a big publication that came out this week. I find the phenomenon of tech-billionaire funding for things like this, asteroid mining, low-cost orbital access and the like very encouraging. (And of course, the Gates Foundation is doing a lot in more earthbound pursuits).

The Wall Street Journal reveals what is apparently a rather ill-kept secret: most firms funded by venture capital fail. "Most", as in about 3 out of 4. That's a loose definition, though - as the article says, if you're talking total wipeout of capital, then that's about one third of them. If you're talking about failing to see the projected return in the projected time, well, that's over 90%. But it's all about the ones that succeed, just like the drug business.

The Royal Society of Chemistry, in a rather self-congratulatory press release, pledges money to help authors publish their work open-access in RSC journals. The UK government is putting money into this, but no one's sure if it'll be enough.

Do you want to make this compound? No? Neither do I. Especially not when they turn around and stick three more nitro groups onto it.

Comments (12) + TrackBacks (0) | Category: Business and Markets | The Central Nervous System | The Scientific Literature

September 19, 2012

The American Chemical Society's Lawsuit Problem

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Posted by Derek

Since we've been talking about the ACS around here recently, I wanted to highlight a decision in a long-running court case the society has been involved in, American Chemical Society v. Leadscope. Rich Apodaca has a summary here of the earlier phases of the suit, which is now in its tenth year in the courts. Basically, three employees of Chemical Abstracts left to form their own chemical information company, and ended up with a patent on a particular variety of software that would display structure-activity and structure-property relationships. The ACS felt that this was too similar to the (discontinued) Pathfinder software they'd developed, and sued.

The ACS lost in a jury trial - in fact, they did more than just lose. The jury found that the society had competed unfairly, filing suit maliciously and defaming Leadscope in the process, and they awarded the latter company $26.5 million in damages. The ACS then lost in the Court of Appeals (and the damages were increased). So they took things all the way to the Ohio Supreme Court, and now they've lost there, too. The defamation ruling (and award) was reversed, and will be vacated by the lower court, but the finding of unfair competition stands. It looks like the society still owes $26.5 million. As this post by an IP lawyer shows, they were going all out:

As for the issue of ACS's subjective intent, the Supreme Court found ample support for the jury's finding that ACS had the intent to injure Leadscope and its founders. It noted that ACS's president had closely monitored Leadscope and had even sent out an email to then-Ohio-Governor Robert Taft to abort a visit by the governor to Leadscope's offices. ACS's former information technology director also provided damaging testimony documenting ACS's president's hostility towards Leadscope. In addition, ACS took actions or made statements that interfered with Leadscope's ability to get funding (for example, by dissuading an venture capitalist interested in investing in Leadscope by telling him that there were legal issues with Leadscope's technology) and took actions in the litigation to disrupt Leadscope's ability to get insurance coverage for the dispute.

As detailed here at ChemBark, it's not like there's been a lot of coverage about this (I've never written about it myself). These are things that every member of the ACS should at least be aware of, but it's not like the ACS is going to do that job, for obvious reasons. One of the main venues for such stories would be. . .Chemical and Engineering News, so that's not going to happen. And it's not a story that resonates much with a general newspaper/magazine readership, so what does that leave us with? Well, mentions like that Nature News article to get the word out, and the blogs to go into the details.

That ChemBark post has a whole series of questions that would be very much worth answering. How the the ACS get into this fix in the first place? Was the original suit ill-advised? How much will that $26.5 million affect the society's finances - is that a big deal, or not? How much further money went down the drain in legal fees along the way? Are there any lessons to be learned from all this, or could the same thing start happening again next month?

And beyond those immediate questions, there are the bigger ones that the ACS (and other scientific societies) should be asking. Can a single entity be (A) a publisher of a large stable of high-profile scientific journals, and (B) the curator and disseminator of the (very profitable) primary database of all the reported chemical matter in the world, and (C) the voice of its own membership, who are simultaneously paying money for access to A and B, and (D) the lobbying organization for chemistry in general, as well as (E) a scientific society dedicated to the spread of knowledge? I'm not sure that all these are possible, at the same time, for the same organization. But sites like ChemBark, and this one, and the rest of the chemical blogworld) are the only places that seem to be available to talk about these things.

Comments (33) + TrackBacks (0) | Category: Chemical News | Patents and IP

September 18, 2012

Boehringer Ingelheim Closing Laval Site

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Posted by Derek

I've heard from more than one person with knowledge of the situation that BI has announced that they'll be closing their Laval site next March. Montreal's drug R&D culture has been taking some major hits the last few years, and this just piles on some more.

Update: the story is now out on the wires, and it looks like this is part of the company getting completely out of antivirals. 170 employees to be affected at Laval.

Comments (18) + TrackBacks (0) | Category: Business and Markets

Going After the Big Cyclic Ones

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Posted by Derek

I wrote last year about macrocyclic compounds and their potential as drugs. Now BioCentury has a review of the companies working in this area, and there are more of them than I thought. Ensemble and Aileron are two that come to mind (if you count "stapled peptides" as macrocycles, and I think they should). But there are also Bicycle, Encycle, Lanthio, Oncodesign, Pepscan, PeptiDream, Polyphor, Protagonist, and Transzyme. These companies have a lot of different approaches. Many of them (but not all) are using cyclic peptides, but there are different ways of linking these, different sorts of amino acids you can use in them, and so on. And the non-peptidic approaches have an even wider variety. So I've no doubt that there's room in this area for all these companies - but I also have no doubt that not all these approaches are going to work equally well. And we're just barely getting to the outer fringes of sorting that out:

While much of the excitement over macrocycles is due to their potential to disrupt intracellular protein-protein interactions, every currently disclosed lead program in the space targets an extracellular protein. This reality reflects the challenge of developing a potent and cell-penetrant macrocyclic compound.

Tranzyme and Polyphor are the only companies with macrocyclic compounds in the clinic. Polyphor’s lead compound is POL6326, a conformationally constrained peptide that antagonizes CXC chemokine receptor 4 (CXCR4; NPY3R). It is in Phase II testing to treat multiple myeloma (MM) using autologous transplantation of hematopoietic stem cells.

Tranzyme’s lead compound is TZP-102, an orally administered ghrelin receptor agonist in Phase IIb testing to treat diabetic gastroparesis.

Two weeks ago, Aileron announced it hopes to start clinical development of its lead internally developed program in 2013. The compound, ALRN-5281, targets the growth hormone-releasing hormone (GHRH) receptor.

Early days, then. It's understandable that the first attempts in this area will come via extracellular-acting, iv-administered agents - those are the lowest bars to clear for a new technology. But if this area is going to live up to its potential, it'll have to go much further along than that. We're going to have to learn a lot more about cellular permeability, which is a very large side effect (a "positive externality", as the economists say) of pushing the frontiers back like this: you figure these things out because you have to.

Comments (11) + TrackBacks (0) | Category: Drug Development | Pharmacokinetics

Rearrange Those Chemists

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Posted by Derek

See Ahr Oh has a handy map of all the big recent faculty moves in the organic chemistry world, to help you keep up. Note that Nicolaou-to-Rice is still a dotted line.

Comments (0) + TrackBacks (0) | Category: Academia (vs. Industry) | Chemical News

September 17, 2012

Pharma Sales Corruption in India. And How.

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Posted by Derek

I work in research. Early research, pulling-stuff-out-of-thin-air type early drug research. I'm about as far from the commercial end of the companies I've worked at as I can be, but it's the commercial end that pays my salary and keeps the labs running.

But that does not mean that everything that drug companies do to sell drugs is therefore justified. Far, far from it. Unfortunately, I have another entry today that will go into my category tag marked "The Dark Side". It's on drug sales tactics in India, which are explored by Frederik Joelving in this article at Reuters. It is not pretty:

The Abbott guide -- reps say the company produces them regularly -- is evidence of a larger problem in India. In interviews with Reuters, dozens of doctors, drug reps and other healthcare insiders said domestic and multinational drug makers routinely shower Indian doctors with gifts, posh junkets abroad, and cash payments disguised as consultancy or other types of fees.

"Indian CRM," or customer-relationship management, is what industry insiders call this system of inducements. None of the doctors or reps who described their participation in this trade would speak on the record. Under Indian law, doctors are prohibited from accepting cash, gifts or travel from drug companies. Still, enforcement is rare, and drug makers may lavish gifts on doctors with impunity, though their home countries may punish the practice.

In a country where doctors often make less than $10,000 a year, it can be an effective strategy.

The drug reps apparently have entire catalogs, with the incentive gifts laid out - a coffeemaker for this drug at this prescription level, a new vacuum cleaner over here, cookware, an invitation to a "conference" in Thailand, what have you. And the indications are that even these gifts are being replaced by more direct inducements, such as sheer cash. That's paid out for being part of a "postmarketing study" that no one controls, whose numbers no one pays attention to, and whose only purpose is to provide cover to pay people off:

Doctors and reps say that often, companies use these studies as cover for paying doctors to prescribe the drugs under study. According to one Abbott rep, the company doesn't pay doctors if sales at nearby pharmacies don't increase.

A doctor who has done post-marketing studies in India says the companies rarely monitor the studies or check the data. "We all understand that post-marketing studies are not really true studies," says the doctor, a diabetes specialist at a Calcutta hospital. They're "just a way to offer an honorarium. So we also don't take them seriously."

Several companies are named in the article - Abbott, Ranbaxy, local Indian drug makers - but the strong impression one gets is that this is how everyone is doing business there, and has for a long time. And that's a major problem. The sales and marketing people in such situations take this as normal, and no one's shocked or upset. They should be, though. Treating this sort of thing as no big deal is bad for the culture of a company, and it's obviously not saying anything good about Indian business culture, either.

I think that there are three levels of corruption. These are distinctions I worked out a while back; see if they make sense. Level 1 is paying people to do something that they wouldn't normally do. Get me good tickets, bump me to the front of the line, that sort of thing. Level 2 is paying people just to do what was supposed to be their job in the first place (but which they won't actually perform unless the honorarium is coming). And Level 3 is the worst - that's when you're paying them not to harm you. A protection racket, in other words, whether it's run by the mob or some Russian regulatory agency that might just enforce some little-known tax laws on you if you don't play ball.

This Indian drug-rep stuff is Level 1 for sure, and probably some Level 2 as well. It wouldn't surprise me at all if there weren't some doctors who wouldn't bother to prescribe a given medicine at all - medical judgement be damned - if the sales reps hadn't provided the goods. That's what I mean when I say that no one comes out the better for this - not the companies, not the doctors, not the patients, not the country. India is full of people who realize that the country is being held back by this sort of corruption, that it's a deadweight loss compared to not having to bribe everyone all the time.

But drug companies are supposed to be full of people who realize that this sort of thing is wrong. That's a culture of corruption for you, though: paying people off with toasters and trips to Thailand is how you make your numbers, and if you don't make your numbers, well, they'll find someone who will. Don't feel like lugging around a sack of kitchen gadgets and consumer electronics? Don't be a drug rep in India - simple.

No, this whole thing is disturbing and disgusting. As I said, I spend my time back in early research, thinking up ideas that might turn into a drug one day. It would not make me happy, to put it mildly, to think of a drug that I'd had a part in discovered being flogged via sleazy vacation offers and sets of cookware dumped on a doctor's office floor. It's my hope that articles like the Reuters one will bring enough attention (and be the source of enough controversy and shame) to start making a difference.

Comments (29) + TrackBacks (0) | Category: The Dark Side

Another One of Those Startling Molecular Images

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Posted by Derek

There's a paper out in Science from a team led by the IBM-Zürich folks, who have been pushing the capabilities of atomic-force microscopy for some time now. These are the people who published the paper in 2009 with those images of pentacene, and now they're back with even higher resolution.
One of their images is shown here. This is a big polycyclic aromatic hydrocarbon, hexabenzocoronene. One of the things that students note when they first try drawing such things is where the "holes" are. Aromatic benzene rings are special (different electron densities, different bond lengths), and if you connect one to another by a single bond (biphenyl), that connecting bond is of ordinary length. But a structure like this one - is it six benzene rings connected by a network of those ordinary bonds? Or are the electrons spread out over the whole surface in a great big delocalized cloud? Or something in between?

Calculations suggest that "in between, but still different" is the right answer, with some of the bonds having more double-bond character than others. And that's what this paper has determined by reaching down and feeling the bonds with an AFM tip. There's a single CO molecule at the end of the probe, and they've gotten to the point where they can see that they get greater sensitivity if that carbon monoxide molecule is tilted over rather than pointing straight down. I am not making that up. Running this single-molecule finger over the surface of hexabenzocoronene gives you the images shown.

"A" is the structure of the molecule, with the two different kinds of bond (i-bonds and j-bonds) noted. "B" is an AFM image at a constant height of 0.35 angstrom, which is really putting your atomic thumb down. The dark parts of the image correspond to attractive forces (van der Waals), and the light parts correspond to repulsive push-back. In this case, the pushback is due to the Pauli exclusion principle - those electrons cannot occupy the same quantum states, and they are quite adamant about that when you try to force them together. The electron density is highest around the outer part of the structure, but you can clearly see the bonds all the way through the internal structure as well. Take a look at the central aromatic ring - its bonds show up more more clearly than the bonds leading out from it, reflecting the greater electron density in there. "C" is an AFM image at 3.5A height in a "pseudo-3d representation", and "D" is the calculated electron density in between these two heights (at 2.5A above the molecule). Note that the two different kinds of bonds are also apparent in panel C, where some of them are brighter and shorter.

This kind of thing continues to give me a funny feeling when I read about it. Actually using things like Pauli repulsion to make pictures of molecules, well. . .maybe I am living in someone's science fiction novel, at that.

Comments (16) + TrackBacks (0) | Category: Chemical News

September 14, 2012

Chemistry in the Quantum Vacuum. No, Really.

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Posted by Derek

When I was clearing a space on my desk the other day, I came across this paper, which I'd printed several months ago to read later. Later's finally here! A brief look at the manuscript will make clear why I didn't immediately dig into it - it's titled "Modifying Chemical Landscapes by Coupling to Vacuum Fields", and it's about as physics-heavy as anything that Angewandte Chemie would be willing to publish. The scary part is, this is one of a pair of papers from the same group (Thomas Ebbesen's at Strasbourg), and it's the other one that really gets into the physics. (If you can't get the first paper, here's a summary of it, the only mention I've been able to find of this work).

But it's worth a bit of digging, because this is very strange and interesting work. So bear with me for a paragraph - I always thought that someone should write a textbook titled "Quantum Mechanics: A Hand-Waving Approach", and that's what you're about to get here. The theory tells us, among many other weird things, that the vacuum between molecules is not what we might think it is. That's more properly the quantum electrodynamic vacuum, the ground state of electromagnetic fields. Because the Planck constant is not zero - tiny, but crucially not zero - the QED vacuum is not the empty nothingness that we think of classically. It's a dielectric, it's diamagnetic, and its properties can be altered. The theory that tells us such odd things is to be taken very seriously indeed, though, since it has made some of the most detailed and accurate predictions in the history of science.

And the vacuum-field fluctuation part of the theory has to be taken very seriously, too, because these effects have actually been measured. This was first accomplished via the Lamb shift and the Casimir effect is the latest poster child. That relates to the properties of the vacuum between two very closely spaced physical plates, and we're now to the point, technologically, where we actually make structures of this kind, measure their sizes and compositions, and determine what's going on inside them.

So what, those few of you who are still reading would like to know, does this have to do with chemistry? Well, when a real molecule is placed between such plates, its energy levels behave in strange ways. And this latest paper demonstrates that with a photochemical rearrangement - the reaction rates change completely depending on whether or not the starting material is confined in the right sort of space, and they change exactly as the cavity is tuned more closely to the absorption taking place. In effect, the molecule is now part of a completely new system (molecule-plus-cavity), and this new system has different energy levels - and can do different chemistry.

The photochemistry shown is not exciting per se, but the fact that it can be altered just by putting the molecule in a very tiny box is exciting indeed:

The rearrangement of the molecular energy levels by coupling to the vacuum field has numerous important consequences for molecular and material sciences. As we have shown here, it can be used to modify chemical energy landscapes and in turn the reaction rates and yields. Strong coupling can either speed up or slow down a reaction depending on the reorganization of specific energy levels relative to the overall energy landscape. Both rates and the thermodynamics of the reaction will be modified. . .The coupling was done here to an electronic transition but it could also be done to a specific vibrational transition for instance to modify the reactivity of a bond. In this way it can be seen as analogous to a catalyst which changes the reaction rate by modifying the energy landscape.

I look forward to seeing how this field develops. If we end up being able to make reactions go the way we want them to by coupling our starting materials to actual fabric of space, I will officially decide that I am, in fact, living in someone's science fiction novel, and I will be very happy about that. I can picture a vacuum-field flow chemistry machine, pumping reactants through various ridiculously small and convoluted lattices, as someone turns a chrome-plated crank on the side to adjust the geometry of the cavities to change the product distributions. OK, there are perhaps a couple of engineering challenges there, but you get the idea.

And speaking as an organic chemist, I have a few other questions: can these vacuum field effects occur in some of the other confined spaces that we're more used to thinking about? The insides of zeolites, for example? The interior of a cyclodextrin? Between sheets of graphene? Inside the active site of an enzyme? I'm sure that there are reasons why not all of these would be able to show such an effect (irregular geometry, just to pick one), but it does make you wonder.

Comments (24) + TrackBacks (0) | Category: Chemical News

Walking Away From the ACS

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Posted by Derek

Here's a look at the scientific journal situation from the viewpoint of the people who have to shell out the money for institutional subscriptions. This librarian (from SUNY-Potsdam) ended up deciding that the American Chemical Society journal package just cost too much, especially for an institution of her size:

We also learned that their base price and pricing model, when applied to much larger institutions, did not produce the same unsustainable pricing – I cannot provide numbers, as they are marked SUNY Confidential, but I can easily say that what our ARL peers pay for ACS in support of their doctoral programs is, in my estimation, in no way fair or reflective of the usage, FTE, or budgets of those institutions as compared to the pricing offered my institution for my usage, FTE, and budgets. It seems to me that the tiered increases may be fair and be reflective, but the problem lies with the base price underlying their pricing model. That base price is unsustainable for small institutions. And, unfortunately, the ACS sales team is not currently interested in negotiating on that fact. In response to any suggestions of ways that SUNY or campuses might collaborate or negotiate to reach a place where we could sustain our subscriptions – one which might well be applied to other campuses, other consortia by ACS – we were repeatedly told “but that’s not our pricing model.”

Wouldn't want to upset the pricing model, that's for sure. The slow earthquake in scientific publishing continues to rumble on.

Comments (50) + TrackBacks (0) | Category: The Scientific Literature

September 13, 2012

ENCODE And What It All Means

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Posted by Derek

You'll have heard about the massive data wave that hit (30 papers!) courtesy of the ENCODE project. That stands for Encyclopedia of DNA Elements, and it's been a multiyear effort to go beyond the bare sequence of human DNA and look for functional elements. We already know that only around 1% of the human sequence is made up of what we can recognize as real, traditional genes: stretches that code for proteins, have start and stop codons, and so on. And it's not like that's so straightforward, either, what with all the introns and whatnot. But that leaves an awful lot of DNA that's traditionally been known by the disparaging name of "junk", and sure it can't just be that - can it?

Some of it does its best to make you think that way, for sure. Transposable elements like Alu sequences, which are repeated relentlessly hundreds of thousands of times throughout the human DNA sequence, must either be junk, inert spacer, or so wildly important that we just can't have too many copies of them. But DNA is three-dimensional (and how), and its winding and unwinding is crucial to gene expression. Surely a good amount of that apparently useless stuff is involved in these processes and other epigenetic phenomena.

And the ENCODE group has indeed discovered a lot of this sort of thing. But as this excellent overview from Brendan Maher at Nature shows, it hasn't discovered quite as many as the headlines might lead you to think. (And neither has it demolished the idea that all the 99% of noncoding DNA is junk, because you can't find anyone who believed that one, either). The figure that's in all the press writeups is that this work has assigned functions for 80% of the human genome, which would be an astonishing figure on several levels. For one thing, it would mean that we'd certainly missed an awful lot before, and for another, it would mean that the genome is a heck of a lot more information-rich than we ever thought it might be.

But neither of those quite seem to be the case. It all depends on what you mean by "functional", and opinions most definitely vary. See this post by Ed Yong for some of the categories. which range out to some pretty broad, inclusive definitions of "function". A better estimate is that maybe 20% of the genome can directly influence gene expression, which is very interesting and useful, but ain't no 80%, either. That Nature post provides a clear summary of the arguments about these figures.

But even that more-solid 20% figure is going to keep us all busy for a long time. Learning how to affect these gene transcription mechanisms is going should be a very important route to new therapies. If you remember all the hype about how the genome was going to unlock cures to everything - well, this is the level we're actually going to have to work at to make anything in that line come true. There's a lot of work to be done, though. Somehow, different genes are expressed at different times, in different people, in response to a huge variety of environmental cues. It's quite a tangle, but in theory, it's a tangle that can be unraveled, and as it does, it's going to provide a lot of potential targets for therapy. Not easy targets, mind you - those are probably gone - but targets nonetheless.

One of the best ways to get a handle on all this work is this very interesting literature experiment at Nature - a portal into the ENCODE project data, organized thematically, and with access to all the papers involved across the different journals. If you're interested in epigenetics at all, this is a fine place to read up on the results of this work. And if you're not, it's still worth exploring to see how the scientific literature might be presented and curated. This approach, it seems to me, potentially adds a great deal of value. Eventually, the PDF-driven looks-like-a-page approach to the literature will go extinct, and something else will replace it. Some of it might look a bit like this.

Note, just for housekeeping purposes - I wrote this post for last Friday, but only realized today that it didn't publish, thus the lack of an entry that day. So here it is, better late, I hope, than never. There's more to say about epigenetics, too, naturally. . .

Comments (16) + TrackBacks (0) | Category: Biological News | The Scientific Literature

September 12, 2012

Honking, Squawking Chemical Ignorance

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Posted by Derek

If you would like to see one of the most idiotic, cloth-headed attempted "explanations" of a chemical structure ever, take yourself to this wonder-rejuvenating-skin-treatment site. And learn what can be accomplished if you take the time, and the effort, to draw the structure of phenol the right way. I am not responsible if you hurt yourself while burying your face in your hands, especially after reading that table in the lower right-hand portion of the page. Spotted by Kevin Booker-Milburn, via Twitter

Comments (44) + TrackBacks (0) | Category: Snake Oil

K. C. Nicolau, Rice University, Six Million Dollars, And Malevolent Aliens

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Posted by Derek

Well, an alert commenter to this post sent along this link to the Cancer Prevention Research Institute of Texas grant site. And if you search for the phrase "R12KCN", you'll see six million dollars set aside for "Recruitment of Established Faculty", which Nicoloau's name attached.

So if this is going to happen, is it a good idea? I'm not asking if it's a good idea for K. C. Nicoloau; he's more than capable of looking after his own career. Is it a good idea for Rice, and for the CPRIT? The answer to that one depends on what everyone is looking for. If Rice is looking to make a big splash, that'll work just fine. But as another comment a bit further down in that above thread notes, this would be a departure for their chemistry department, because they'd actually de-emphasized organic synthesis a while back. Bringing in KCN will certainly re-emphasize it for them, if that's what they're after.

It's not where I would put my money, but (fortunately) I am not in charge of laying out millions to stock up a chemistry department. I've written several times (most recently here) about what I think of total synthesis at this point in the history of the science. If malevolent aliens suddenly filled our skies, threatening to vaporize the planet if we did not synthesize maitotoxin, I would unhesitatingly vote to give K. C. Nicolaou unlimited funding. That's what he does, and he's damn good at it. I just don't think - without the alien pressure and all - that it provides as much return for the time and money as other areas of science.

Comments (33) + TrackBacks (0) | Category: Chemical News

September 11, 2012

Nicolaou Moving? Others?

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Posted by Derek

There's a rumor making the rounds that K. C. Nicolaou is leaving Scripps (La Jolla), with the most often-mentioned destination being Rice University. That's striking many people as a bit unlikely, unless Rice has decided to really throw the money (and facilities spending) around, and has decided to start off with a big splash. But there is at least a bit of a Scripps-to-South migration going on, with M. G. Finn heading to Georgia Tech. So we shall see. . .anyone heard more?

Comments (64) + TrackBacks (0) | Category: Chemical News

Careers, And Those Words "Stuck" and "Advance"

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Posted by Derek

A recent comment to another post prompts this entry. Regarding getting a chemistry PhD and getting a job, it reads:

. . .However, transitioning into corporate pharma was a big if not bigger challenge in some ways. It took a while to figure out how the system works and how to advance one's career and not get stuck in the lab.

Now this is a touchy subject, and it's two words in it that make it so: "advance" and "stuck". Pick one hundred chemists who start out in, say, industrial drug research at any given time (I know, bear with me - it's a thought experiment). Now observe them at the five year mark, the ten, and the twenty. What will you find? Some of them will no longer be employed, for sure - recent years make that certain, but honestly, it's always been certain. Some of that, remember, is voluntary. Some people find out, in any profession (once they start practicing it) that it's not actually what they want to do with their lives. It's better to find that out earlier than later. Or something that's clearly better might come along; there are any number of reasons for people to exit a field on their own power. But others true will have been acted on by an outside force, whether that force is their own difficulty in holding on to their position, or the industry's difficulty in holding on to as many people as it used to.

So among those still employed, what will you have? Some of them will have more direct reports than others, or more responsibility in other ways. People's abilities, opportunities, and motivations vary. As time goes on, some of the initial cohort will have definitely moved "out of the lab". But there are different reasons for this. The most common is what's usually called something like "the managerial track". Depending on the company, it's often the case that as people move to higher positions on the org chart, that they'll spend less time actually in the lab as opposed to their offices. In the traditional European drug research labs (especially the German and Swiss ones), this process started very quickly, sometimes on day one. And in general, the larger the company, the more likely it is that people have desk-only jobs as they move along.

But most companies like this also have a "scientific track", although it's sometimes used as a bit of dumping ground for people who (for whatever reason) are definitely not on the managerial track. That does tend to cut into the definition between the two, but the idea is to have somewhere to advance/promote people who don't want to head in the desk/management direction. It's here, I think, that the hard feelings start, because of this blurred boundary.

It's safe to say that some people who move into the managing-the-organization side of the business don't miss the lab work all that much, although some of them certainly do. And it's also safe to say that some of the people who stay on the scientific side would very much rather not have to deal with a stack of performance reviews, budget spreadsheets, making sure that everyone's up to date in the internal training database, and the like - but then again, some of them wouldn't mind that stuff at all, if anyone would give them a chance to mind it. To further complicate things, not everyone on the managerial side of the business is necessarily a good manager, just as not everyone on the lab side of it is a wonderful scientist. And people with longtime desk/office jobs are sometimes heard to say that they miss lab work, in a sort of "good old days" tone.

So you can get some pretty dismissive stuff, from both sides. These would include (but are not limited to) statements about being someone being "stuck in the lab" (as opposed to doing the really important work), or someone else being nothing but a paper pusher who's forgotten how research works (or perhaps never really knew to start with). I try to stay away from those sorts of statements, myself, but everyone in industry will know the sort of thing I'm talking about.

My own preferences? I have a hood, and I work in it. I'm not there all the time, but I'm expected (as are others like me) to produce in the lab as well as at my desk. And I do spend time at the desk, too, although I try to spend it on scientific issues - how do we prosecute the project for Target X? What are the chances for Project Y, and what do we do if it doesn't work out? What technology do we have (or does anyone have) to go after Target Z? Managerially, I've never had a long list of direct reports, nor a list of people reporting to me who also have people reporting to them, etc. I've been, it's fair to say, on the scientific ladder. But "stuck in the lab" is not a phrase I've ever applied to myself.

The key, I think, is to continue to learn and to keep up, no matter which side of the divide you might be. You should be performing at a level that you couldn't have earlier in your career, either way - dealing with issues that you wouldn't have been able to handle, bringing your experience to bear on new situations. The danger in having been around the block a number of times is that you can start to feel as if you know more than you do, or that you've seen pretty much everything before (neither of those is true). But you should definitely know more than you used to!

Comments (31) + TrackBacks (0) | Category: Life in the Drug Labs

September 10, 2012

Nobel Season Begins!

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Posted by Derek

As we head into Nobel Season, Chembark and Wavefunction have their latest odds up. The biology side of the chemistry prize seems to be getting a lot of betting this year, with nuclear hormone signaling, chaperone proteins, oncogenes, Western/Southern blotting, and various bioinorganic discoveries all being mentioned. I'll do a full post on my own predictions (and what I wouldn't like to see get the prize), but there's a lot of good material in those two posts to start thinking about.

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

Geron, And The Risk of Cancer Therapies

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Posted by Derek

Geron's telomerase inhibitor compound, imetalstat, showed a lot of interesting results in vitro, and has been in Phase II trials all this year. Until now. The company announced this morning that the interim results of their breast-cancer trial are so unpromising that it's been halted, and that lung cancer data aren't looking good, either. The company's stock has been cratering in premarket trading, and this stock analyst will now have some thinking to do, as will the people who followed his advice last week.

I'm sorry to see the first telomerase inhibitor perform so poorly; we need all the mechanisms we can get in oncology. And this is terrible news for Geron, since they'd put all their money down on this therapeutic area. But this is drug discovery; this is research: a lot of good, sensible, promising ideas just don't work.

That phrase comes to mind after reading this article from the Telegraph about some Swedish research into cancer therapy. It's written in a breathless style - here, see for yourself:

Yet as things stand, Ad5[CgA-E1A-miR122]PTD – to give it the full gush of its most up-to-date scientific name – is never going to be tested to see if it might also save humans. Since 2010 it has been kept in a bedsit-sized mini freezer in a busy lobby outside Prof Essand's office, gathering frost. ('Would you like to see?' He raises his laptop computer and turns, so its camera picks out a table-top Electrolux next to the lab's main corridor.)
Two hundred metres away is the Uppsala University Hospital, a European Centre of Excellence in Neuroendocrine Tumours. Patients fly in from all over the world to be seen here, especially from America, where treatment for certain types of cancer lags five years behind Europe. Yet even when these sufferers have nothing else to hope for, have only months left to live, wave platinum credit cards and are prepared to sign papers agreeing to try anything, to hell with the side-effects, the oncologists are not permitted – would find themselves behind bars if they tried – to race down the corridors and snatch the solution out of Prof Essand's freezer.

(By the way, does anyone have anything to substantiate that "five years behind Europe" claim? I don't.) To be sure, Prof. Essand tries to make plain to the reporter (Alexander Masters) that this viral therapy has only been tried in animals, that a lot of things work in animals that don't work in man, and so on. But given Masters' attitude towards medical research, there's only so much that you can do:

. . .Quacks provide a very useful service to medical tyros such as myself, because they read all the best journals the day they appear and by the end of the week have turned the results into potions and tinctures. It's like Tommy Lee Jones in Men in Black reading the National Enquirer to find out what aliens are up to, because that's the only paper trashy enough to print the truth. Keep an eye on what the quacks are saying, and you have an idea of what might be promising at the Wild West frontier of medicine. . .

I have to say, in my experience, that this is completely wrong. Keep an eye on what the quacks are saying, and you have an idea of what might have been popular in 1932. Or 1954. Quacks seize onto an idea and never, ever, let it go, despite any and all evidence, so quackery is an interminable museum of ancient junk. New junk is added all the time, though, one has to admit. You might get some cutting-edge science, if your idea of cutting-edge is an advertisement in one of those SkyMall catalogs you get on airplanes. A string of trendy buzzwords super-glued together does not tell you where science is heading.

But Masters means well with this piece. He wants to see Essend's therapy tried out in the clinic, and he wants to help raise money to do that (see the end of the article, which shows how to donate to a fund at Uppsala). I'm fine with that - as far as I can tell, longer shots than this one get into the clinic, so why not? But I'd warn people that their money, as with the rest of the money we put into this business, is very much at risk. If crowdsourcing can get some ideas a toehold in the clinical world, I'm all for it, but it would be a good thing in general if people realized the odds. It would also be a good idea if more people realized how much money would be needed later on, if things start to look promising. No one's going to crowdsource a Phase III trial, I think. . . .

Comments (12) + TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Development

September 6, 2012

Databases and Money

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Posted by Derek

The NIH has been cutting back on its funding (via the National Libraries of Medicine) for a number of external projects. One of those on the chopping block is the Biological Magnetic Resonance Bank (BMRB), at Wisconsin:

The BMRB mission statement is to “collect, annotate, archive and disseminate (worldwide in the public domain)” NMR data on biological macromolecules and metabolites, to “empower scientists” and to “support further development of the field.” Despite its indisputable success in achieving these goals, the BMRB is facing serious funding challenges.

Since 1990, the BMRB has received continuous support from the National Library of Medicine (NLM), at the US National Institutes of Health, in the form of five-year grants. However, the BMRB obtained its latest grant renewal in 2009, accompanied by a sharp reduction in the funding level. It was also to be the last renewal, as the NLM announced that funding for all external centers would be phased out as their grants expire. Thus, as of today, the BMRB has no means of financial support after September 2014.

That editorial link above, from Nature Structural and Molecular Biology, also has a several other database projects formerly supported by the NLM. These are far enough outside my own field that I've never had call to use any of them as a medicinal chemist, but (as that last link shows) they are indeed used, and by plenty of researchers.

This problem won't be going away, since the volume of data produced these days shows no sign of any inflection points. Molecular genetics, protein biology, and structural biology in general are producing vast piles of material. Having as much of it as possible brought together and curated is clearly in the best interest of scientific research - but again, who pays?

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

Graphical Abstract Tedium

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Posted by Derek

Scrolling through my journal RSS feeds, a question occurs to me. What's the biggest cliché, the most overused trope in graphic abstracts? My nomination is the "row of glowing vials" to illustrate some new fluorescent/luminescent sensor molecule. Nothing wrong with a row of glowing vials per se, but man, has that image ever been done to death. (I'm just glad that I'm not working on anything of the kind, so I don't have to figure out what to show instead). Your nominations? Just think of what makes you grit your teeth as you glance over the journal table of contents, even before you've read the title of the paper, and you'll have it.

Update: as mentioned in the comments, if you want the TOC graphics that are each. . .special. . .in their own way, then look no further than TOCROFL.

Comments (19) + TrackBacks (0) | Category: The Scientific Literature

Accelerated Approval And Its Discontents

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Posted by Derek

This may sound a little odd coming from someone in the drug industry, but I have a lot of sympathy for the FDA. I'm not saying that I always agree with them, or that I think that they're doing exactly what we need them to do all the time. But I would hate to be the person that would have to decide how they should do things differently. And I think that no matter what, the agency is going to have a lot of people with reasons to complain.

These thoughts are prompted by this article in JAMA on whether or not drug safety is being compromised by the growing number of "Priority Review" drug approvals. There are three examples set out in detail: Caprelsa (vandetanib) for thyroid cancer, Gilenya (fingolimod) for multiple sclerosis, and the anticoagulant Pradaxa (dabigatran). In each of these accelerated cases, safety has turned out to be more of a concern than some people expected, and the authors of this paper are asking if the benefits have been worth the risks.

Pharmalot has a good summary of the paper, along with a reply from the FDA. Their position is that various forms of accelerated approval have been around for quite a few years now, and that the agency is committed to post-approval monitoring in these cases. What they don't say - but it is, I think, true - is that there is no way to have accelerated approvals without occasional compromises in drug safety. Can't be done. You have to try to balance these things on a drug-by-drug basis: how much the new medication might benefit people without other good options, versus how many people it might hurt instead. And those are very hard calls, which are made with less data than you would have under non-accelerated conditions. If these three examples are indeed problematic drugs that made it through the system, no one should be surprised at all. Given the number of accelerated reviews over the years, there have to be some like this. In fact, this goes to show you that the accelerated review process is not, in fact, a sham. If everything that passed through it turned out to be just as clean as things that went through the normal approval process, that would be convincing evidence that the whole thing was just window dressing.

If that's true - and as I said, I certainly believe it is - then the question is "Should there be such a thing as accelerated approval at all?" If you decide that the answer to that is "Yes", then the follow-up is "Is the risk-reward slider set to the right place, or are we letting a few too many things through?" This is the point the authors are making, I'd say, that the answer to that question is "Yes", and we need to move the settings back a bit. But here comes an even trickier question: if you do that, how far back do you go before the whole accelerated approval process is not worth the effort any more? (If you try to make it so that nothing problematic makes it through at all, you've certainly crossed into that territory, to my way of thinking). So if three recent examples like these represent an unacceptable number (and it may be), what is acceptable? Two? One? Those numbers, but over a longer period of time?

And if so, how are you going to do that without tugging on the other end of the process, helping patients who are waiting for new medications? No, these are very, very hard questions, and no matter how you answer them, someone will be angry with you. I have, as I say, a lot of sympathy for the FDA.

Comments (7) + TrackBacks (0) | Category: Drug Development | Regulatory Affairs | Toxicology

September 5, 2012

Merck (Germany) Cuts Back

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Posted by Derek

If you haven't heard, Merck KGgA has announced that they're cutting over a thousand jobs in Germany. They'd already cut back hard in the Merck Serono end of the company, and now comes the rest. . .

Comments (4) + TrackBacks (0) | Category: Business and Markets

More on Getting a Science PhD

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Posted by Derek

An article in Slate on science PhDs and scientific employment has been creating a stir among people who think about such issues. (This topic has come up around here a few times, naturally). It's titled "Is a Science PhD a Waste of Time?", and I'll spare you any suspense and tell you that the author's answer is "No". Scientific unemployment has been exaggerated, says the article, and the degree is pretty much totally worth it.

Chemjobber has his own response to all this, and he brings numbers and citations (rather than anecdotes of unnamed people) to the discussion. But it's the whole thrust of the article that he finds hardest to deal with:

I find Mr. Lametti's essay very frustrating. It is suffused with youthful optimism, which is no substitute for a cold look at the facts. I am surprised at the apparent non-existence of the unemployed scientist, and that there doesn't appear to be anybody older than 35 or so in his essay. Wrestling with the damage caused by layoffs or outsourcing don't seem to be worth his time; you got your Ph.D.! Isn't that wonderful? (You should be able to find another job in a snap!)

Nothing against youthful optimism - I keep some (well-insulated) for use in times of need myself. And if someone really does feel like a career in research is right for them, even after getting well into grad school, they're probably right. If you're a fit with this sort of thing, there may well be no good substitute for it. But anyone who's pursuing that career needs to be as clear-eyed as possible about it and about what's going on in the real world. Optimism and lack of information (willed or not) - that's a recipe for trouble.

Comments (56) + TrackBacks (0) | Category: Graduate School

September 4, 2012

A New Malaria Compound

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Posted by Derek

There have been many headlines in recent days about a potential malaria cure. I'm not sure what set these off at this time, since the paper describing the work came out back in the spring, but it's certainly worth a look.

This all came out of the Medicines for Malaria Venture, a nonprofit group that has been working with various industrial and academic groups in many areas of malaria research. This is funded through a wide range of donors (corporations, foundations, international agencies), and work has taken place all over the world. In this case (PDF), things began with a collection of about 36,000 compounds (biased towards kinase inhibitor scaffolds) from BioFocus in the UK. These were screened (high-throughput phenotypic readout) at the Eskitis Institute in Australia, and a series of compounds was identified for structure-activity studies. This phase of the work was a three-way collaboration between a chemistry team at the University of Cape Town (led by Prof. Kelly Chibale), biology assay teams at the Swiss Tropical and Public Health Institute, and pharmacokinetics at the Center for Drug Candidate Optimization at Monash University in Australia.
An extensive SAR workup on the lead series identified some metabolically labile parts of the molecule over on that left-hand side pyridine. These could fortunately be changed without impairing the efficacy against the malaria parasites. The sulfonyl group seems to be required, as does the aminopyridine. These efforts led to the compound shown, MMV390048, which has good blood levels, passes in vitro safety tests, and is curative in a Plasmodium berghei mouse model at a single dose of 30 mg/kg. That's a very promising compound, from the looks of it, since that's better than the existing antimalarials can do. It's also active against drug-resistant strains, as well it might be (see below). Last month the MMV selected it for clinical development.

So how does this compound work? The medicinal chemists in the audience will have looked at that structure and said "kinase inhibitor", and that has to be where to put your money. That, in fact, appears to have been the entire motivation to screen the BioFocus collection. Kinase targets in Plasmodium have been getting attention for several years now; the parasite has a number of enzymes in this class, and they're different enough from human kinases to make attractive targets. (To that point, I have not been able to find results of this latest compound's profile when run against a panel of human kinases, although you'd think that this has surely been done by now). Importantly, none of the existing antimalarials work through such mechanisms, so the parasites have not had a chance to work up any resistance.

But resistance will come. It always does. The best hope for the kinase-based inhibitors is that they'll hit several malaria enzymes at once, which gives the organisms a bigger evolutionary barrier to jump over. The question is whether you can do that without hitting anything bad in the human kinome, but for the relatively short duration of acute malaria treatment, you should be able to get away with quite a bit. Throwing this compound and the existing antimalarials at the parasites simultaneously will really give them something to occupy themselves.

I'll follow the development of this compound with interest. It's just about to hit the really hard part of drug research - human beings in the clinic. This is where we have our wonderful 90% or so failure rates, although those figures are generally better for anti-infectives, as far as I can tell. Best of luck to everyone involved. I hope it works.

Comments (27) + TrackBacks (0) | Category: Drug Development | Infectious Diseases