About this Author
College chemistry, 1983
The 2002 Model
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: firstname.lastname@example.org
In the Pipeline:
Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline
August 19, 2014
Here's a very good review article in J. Med. Chem. on the topic of protein binding. For those outside the field, that's the phenomenon of drug compounds getting into the bloodstream and then sticking to one or more blood proteins. Human serum albumin (HSA) is a big player here - it's a very abundant blood protein that's practically honeycombed with binding sites - but there are several others. The authors (from Genentech) take on the disagreements about whether low plasma protein binding is a good property for drug development (and conversely, whether high protein binding is a warning flag). The short answer, according to the paper: neither one.
To further examine the trend of PPB for recently approved drugs, we compiled the available PPB data for drugs approved by the U.S. FDA from 2003 to 2013. Although the distribution pattern of PPB is similar to those of the previously marketed drugs, the recently approved drugs generally show even higher PPB than the previously marketed drugs (Figure 1). The PPB of 45% newly approved drugs is >95%, and the PPB of 24% is >99%. These data demonstrate that compounds with PPB > 99% can still be valuable drugs. Retrospectively, if we had posed an arbitrary cutoff value for the PPB in the drug discovery stage, we could have missed many valuable medicines in the past decade. We suggest that PPB is neither a good nor a bad property for a drug and should not be optimized in drug design.
That topic has come up around here a few times, as could be expected - it's a standard med-chem argument. And this isn't even the first time that a paper has come out warning people that trying to optimize on "free fraction" is a bad idea: see this 2010 one from Nature Reviews Drug Discovery.
But it's clearly worth repeating - there are a lot of people who get quite worked about about this number - in some cases, because they have funny-looking PK and are trying to explain it, or in some cases, just because it's a number and numbers are good, right?
+ TrackBacks (0) | Category: Drug Assays | Drug Development | Pharmacokinetics
How many ways do we have to differentiate samples of closely related compounds? There's NMR, of course, and mass spec. But what if two compounds have the same mass, or have unrevealing NMR spectra? Here's a new paper in JACS that proposes another method entirely.
Well, maybe not entirely, because it still relies on NMR. But this one is taking advantage of the sensitivity of 19F NMR shifts to molecular interactions (the same thing that underlies its use as a fragment-screening technique). The authors (Timothy Swager and co-workers at MIT) have prepared several calixarene host molecules which can complex a variety of small organic guests. The host structures feature nonequivalent fluorinated groups, and when another molecule binds, the 19F NMR peaks shift around compared to the unoccupied state. (Shown are a set of their test analytes, plotted by the change in three different 19F shifts).
That's a pretty ingenious idea - anyone who's done 19F NMR work will hear about the concept and immediately say "Oh yeah - that would work, wouldn't it?" But no one else seems to have thought of it. Spectra of their various host molecules show that chemically very similar molecules can be immediately differentiated (such as acetonitrile versus propionitrile), and structural isomers of the same mass are also instantly distinguished. Mixtures of several compounds can also be assigned component by component.
This paper concentrates on nitriles, which all seem to bind in a similar way inside the host molecules. That means that solvents like acetone and ethyl acetate don't interfere at all, but it also means that these particular hosts are far from universal sensors. But no one should expect them to be. The same 19F shift idea can be applied across all sorts of structures. You could imagine working up a "pesticide analysis suite" or a "chemical warfare precursor suite" of well-chosen host structures, sold together as a detection kit.
This idea is going to be competing with LC/MS techniques. Those, when they're up and running, clearly provide more information about a given mixture, but good reproducible methods can take a fair amount of work up front. This method seems to me to be more of a competition for something like ELISA assays, answering questions like "Is there any of compound X in this sample?" or "Here's a sample contaminated with an unknown member of Compound Class Y. Which one is it?" The disadvantage there is that an ELISA doesn't need an NMR (with a fluorine probe) handy.
But it'll be worth seeing what can be made of it. I wonder if there could be host molecules that are particularly good at sensing/complexing particular key functional groups, the way that the current set picks up nitriles? How far into macromolecular/biomolecular space can this idea be extended? If it can be implemented in areas where traditional NMR and LC/MS have problems, it could find plenty of use.
+ TrackBacks (0) | Category: Analytical Chemistry
August 18, 2014
I spent the morning in the lab pretty much destroying whatever I touched: wrong solvents for chromatography, dropping things in the sink, bumping solutions all over the inside of my rota-vap. This is, though, a Monday, so at least I have that to blame. But if everyone started out the week the way I did, then scientific progress came to a juddering halt around 11 AM EST. My hope is that I can be less of a wrecking ball during the rest of the day and start working my way back into positive territory.
+ TrackBacks (0) | Category: Life in the Drug Labs
Here's a look back at the beginnings of ChemDraw, and you won't be surprised to hear that its origins go back to someone (Dave Evans' wife!) who'd had way too much of the old-fashioned style of structure drawing.
As I've mentioned here before, my grad school experience ended up being timed to experience both worlds. For my second-year continuation exam, I had to do the structures the classic way: green plastic template to make the chair and boat cyclohexanes all come out the same, rub-on letters for the atoms. If you wanted to copy a structure, well, you went down to the copier and you copied that structure. And you Frankensteined each scheme together with tape (matte, not shiny) or glue stick to make The Final Copy, rolling it into the typewriter to put in the captions and the text over the arrows. As I've always said, it was, in retrospect, not too far off from incising a buffalo-dung tablet with a sharpened stick and leaving it in the sun to dry.
It was a lot closer to that then it was to ChemDraw, that's for sure. (The sharpened stick would have worked pretty well with those rub-on letter transfers). And this is exactly what happened every time an organic chemist saw it in action:
The program developed little by little in this manner, with Sally channeling the needs of chemists and Rubenstein doing the programming. In July of 1985, ChemDraw premiered at the Gordon Research Conference on Reactions & Processes in New Hampshire. Rubenstein and the Evanses demonstrated it during a break in the conference. Bad weather kept the conferees indoors, so attendance was high.
Stuart L. Schreiber, then a chemistry professor at Yale University, saw the demo and recalls “knowing instantly that my prized drafting board and my obsessive drafting of chemical formulas were over.”
Schreiber holds the distinction of being the first person to purchase ChemDraw. “The impact of seeing ChemDraw on a Macintosh computer was dramatic and immediate,” he says. “There was no doubt that this was going to change the way chemists interact with each other and the rest of the scientific community,” he says. At the time Schreiber was proudly using his Xerox Memorywriter electronic typewriter with two lines of editable text. “The combination of the Macintosh computer and ChemDraw clearly demanded next-day adoption.” He rushed home to New Haven and placed his order.
That's just how it went. Every organic chemist who saw the program in action immediately wanted it; the superiority of the program to any of the manual methods was immediately and overwhelmingly obvious. You hear similar stories about people's reactions to the first spreadsheet program (VisiCalc) in the late 1970s, and for exactly the same reasons. Advances like these need no sales pitch at all - you could demo such things in complete silence for five minutes and people would line up with their money. I can remember seeing ChemDraw for the first time when I was at Duke, and being stunned by the idea of copying and pasting structures, resizing them, rotating them, joining them together, and (especially) saving the damned things for later.
So for my dissertation, which I started writing in late 1987, it was Word (3.02!) and ChemDraw all the way, and I was the first person in Duke's chemistry department to solo with those two for the PhD writeup. I did some of it on a Mac Plus and a lot of it on Mac SEs, switching floppy disks in and out. There was a Mac II down the hall, with a color screen and a 20 MB hard drive, and I really felt like I was on the cutting edge when I used that one. My lone disk with the manuscript in progress went unreadable and unrecoverable after two weeks of intermittent work, which taught me a lifelong lesson about making backups. Although it was a major pain to keep it up, I ended (with not-so-unusual grad student paranoia) by keeping five copies at all times: the current working copy, an extra one in the desk drawer in my lab, one back by my bench, one over in my apartment, and one in the glove compartment of my car.
My PhD advisor was not a computer user himself at the time, though, which led to an interesting scene when I did hand the manuscript over to him some months later (which process was an interesting story in itself, for another time). He got it back to me with a large number of hand-marked corrections, but as I flipped through the pages I realized that almost all of them were the same corrections, flagged every time that they appeared. I saw him that afternoon, and he asked if I'd seen his changes. I had, I told him, and I'd made al the corrections. He looked at me, puzzled, so I told him about the "Find and Replace" command, and he raised his eyebrows and said "That's very. . .convenient, isn't it?" "Sure is," I badly wanted to say. "Welcome to the fun-filled late 20th century, boss. Let's see, what else. . .we landed on the moon in '69. Oh, the Beatles broke up. And. . ."
But I didn't say any of that, of course. You don't go around saying things like that to your professor, especially when you're in the final stages of writing up, not unless you want to face the choice of going back to the lab for a couple more years or asking people if they'd like the Value Meal. No, facing your committee is preferable in every way.
+ TrackBacks (0) | Category: Graduate School
August 15, 2014
There's a post by Peter Bach, of the Center for Health Policy and Outcomes, that's been getting a lot of attention the last few days. It's called "Unpronounceable Drugs, Incomprehensible Prices", and you know what it says.
No, really, you do, even if you haven't seen it. Too high, unconscionable, market can't support, what they can get away with, every year, too high. Before I get to the uncomfortable parts of my own take on this, let me stipulate a couple of things up front: (1) I do think that the industry is inviting trouble for itself by the way it it raising prices. It is in drug companies' short term interest to do so, but long term I worry that it's going to bring on some sort of price-control regimen. (2) Some drug prices probably are too high (but see below for what that means). Big breakthroughs can, at least in theory, command high prices, but not everything deserves to be priced at the level it is.
I was about to say "see below" again, but this paragraph is below, so here goes. Let me quote a bit from Bach's article:
Cancer drug prices keep rising. The industry says this reflects the rising costs of drug development and the business risks they must take when testing new drugs. I think they charge what they think they can get away with, which goes up every year. . .Regardless of the estimate, the pricing of new drugs for cancer and now other common diseases has come unglued from the rationale the industry has long espoused. Instead, pricing is explained by a phenomenon of increasing boldness by the industry against a backdrop of regulators and insurers who have no legal authority to dictate or even propose alternative pricing models.
Bach's first assertion is correct: drug companies are charging what they think they can get away with. In that, they are joined by pretty much every other business in the entire country. I did a post once where I imagined car sales transplanted into the world of drug sales- you couldn't just walk in and buy a car, for example. No, you had to go to a car consultant first, licensed by the state, who would examine your situation and determine the sort of car you needed. Once they'd given you a car prescription, you could then go to a dealer.
Well, we don't have that, but what car companies do charge is, well, what they can get away with. The same as steel companies, soft drink companies, cardboard box companies, grocery stores, and people who are selling their houses. You charge what you think the market will bear. Even people selling basic necessities of life like food and shelter charge what they think the market will bear. It's true that health care does feel different from any of those (a point that I went into in that post linked in the last paragraph), and there's the root of many a problem.
And, some will say, a big difference is that none of these other sellers have patents on their side, the legal right to put the screws on. But remember the flip side of the patent system: the legal certainty that you will lose that pricing power on a set date. The pricing of new drugs is completely driven by their expected patent lifetimes, because almost all the money that the developing company is ever going to make off the drug is going to have to be made during that period.
And sometimes that period isn't very long. The patent clock starts ticking a long time before a drug ever gets on the market; there are often only five to ten years left when it's finally approved for sale. There are other factors, too. Everyone is talking about the price of Sovaldi for hepatitis C, but no as many people have thought about the fact that the drug is, in fact, so effective that it has blown two other recently approved Hep C treatments right out of the market, well before their patent lifetimes had even expired. There really is competition in the drug business, and that sector shows it in action.
Now, what there isn't so much of is competition on price, true. And that's what you do see in the other businesses I named above. There are grocery stores that occupy the "Wonderful Prestigious High Quality" part of the market, and others that occupy the "Low Low Prices Every Day" part. (And interestingly, if you Venn-diagram out what's on the shelves of those two, there's still some overlap, allowing you to watch people paying wildly different prices for blueberries that came off the same truck, not to mention even less perishable stuff like aluminum foil). You don't see this in the drug industry, partly because for patented drugs we're never selling the same blueberries. the same gasoline, or the same khaki trousers. Even the biggest "me-too" drugs still differ from each other to some degree.
And that brings up another point. Bach uses (as his example of pricing in the cancer field) two Alk compounds, Xalkori (crizotinib) from Pfizer and Zykadia (ceritinib) from Novartis. Xalkori was first, and Bach makes a lot of the fact that Zykadia is priced higher, even though he says that Pfizer ran bigger clinical trials, had to work out the associated diagnostic test with the FDA, and launch the new mechanism into the oncology market. Novartis, he says, got to piggy-back on all that, and yet their drug is priced higher. There can be no other reason for that pricing decision, Bach says, other than that they can.
Let's go into some details that Bach's article leaves out. Zykadia is indeed second to market. But the time gap between the two drugs means that Novartis was working on it before they knew that Xalkori worked in the clinic. Bach makes an error here made by many others who have not actually done drug discovery work: the time course of these things is longer than it looks. A screen had to be run against Alk, compounds had to be confirmed, a medicinal chemistry team had to optimize them and make lots of new structures, all of which except one fell by the side of the road. The compound had to go through animal tests for efficacy and safety, and it had to be scaled up and formulated. And so on, and so on. Novartis did not sit back, watch Xalkori succeed, and then decide "Hey, we should get us some of that action, too".
Now Zykadia is, as Bach says, a second-line therapy. But it's approved for patients who do not respond to, or have become intolerant to Xalkori. So this "me-too" drug is, in fact, different enough to work on patients for whom Xalkori has failed. In fact, most patients will start to show relapse inside of a year on Xalkori, so it would appear that most non-small-cell lung cancer patients with multiyear survival are probably going to end up taking both compounds. Cancers mutate quickly, and we need all the options we can get - and guess what, some of those options are going to be second to market, because they can't all be first.
Another point to note is that while Zykadia was indeed approved on the basis of a smaller clinical trial set, that's because it received "breakthrough" designation from the FDA for accelerated review and approval. Startlingly, it actually got approved after Phase I trials alone. (Not bad for what Bach characterizes as a simple copycat drug, by the way). Novartis has run the compound in more clinical trials than that, and they continue to do so. It's not like they slipped in with a mere 163 patients and then trotted off to the FDA while brushing the dust off their hands. To find this out, by the way, you'll want to use "LDK378", the internal Novartis designation for the drug, and I'm passing this information on to Bach for free. Clinicaltrials.gov shows 13 trials in the US when you do that, and there are others outside the country as well.
Bach's article, as mentioned, plays down any differences between these two drugs, saying that "they have not been directly compared". But that's not accurate. Let me quote from that link in the paragraph just above:
As described by Shaw and colleagues in the New England Journal of Medicine, ceritinib has striking activity in ALK-rearranged NSCLC, both in treatment-naïve patients and in those who experienced tumor progression on crizotinib. . .The drug has clear pharmacological advantages over crizotinib. Its surprising level of activity in crizotinib-resistant tumors may be explained by its greater potency and its particular ability to inhibit ALK with gatekeeper mutations that confer resistance to crizotinib.
The two drugs have had a very important comparison: people who are going to die on Xalkori are going to survive longer if they switch to Zykadia. "Me-too" drug, my ass.
But rather than end on that note, tempting as that is, let me circle back to pricing once again. The price for these cancer drugs is not borne by individual patients emptying their piggy banks. It is borne by insurance, both private and government. And drug companies do indeed price their drugs at what the think the insurance plans will pay for them. This is not a secret, and should not be a surprise, and I continue to be baffled by people who react to this with horror and disbelief. Prices appear when you find out what the payers will pay. If Pfizer, Novartis, or Gilead priced their drugs at fifty million dollars a dose, no insurance company would reimburse. But the insurance companies are paying the current prices, and if they believe that they will be put out of business by doing so, they need to stop doing that. And they could.
They will, too, if we in the industry keep pushing them towards doing it. That's our big problem in drug development: our productivity has been too low, and we're making up for it by charging more money. But that can't go on forever. There are walls closing in on us from both sides, and we're going to have to scramble out from between them at some point. Pricing power can only take you so far.
+ TrackBacks (0) | Category: Cancer | Clinical Trials | Drug Prices | Regulatory Affairs | Why Everyone Loves Us
August 14, 2014
A huge amount of what's actually going on inside living cells involves protein-protein interactions. Drug discovery, for obvious reasons, focuses on the processes that depend on small molecules and their binding sites (thus the preponderance of receptor ligands and enzyme inhibitors), but small molecules are only part of the story in there.
And we've learned a fair amount about all this protein-protein deal-making, but there's clearly a lot that we don't understand at all. If we did, perhaps we'd have more compounds that can target them. Here's a very basic topic about which we know very little: how tight are the affinities between all these interacting proteins? What's the usual level, and what's the range? What does the variation in binding constants say about the signaling pathways involved, and the sorts of binding surfaces that are being presented? How long do these protein complexes last? How weak can one of these interactions be, and still be physiologically important?
A new paper has something to say about that last part. The authors have found a bacterial system where protein phosphorylation takes place effectively although the affinity between the two partners (KD) is only around 25 millimolar. That's very weak indeed - for those outside of drug discovery, small-molecule drug affinities are typically well over a million times that level. We don't know how common or important such weak interactions are, but this work suggests that we're going to have to look pretty far up the scale in order to understand things, and that's probably going to require new technologies to quantify such things. Unless we figure out that huge, multipartner protein dance that's going on, with all its moves and time signatures, we're not going to understand biochemistry. The Labanotation for a cell would be something to see. . .
+ TrackBacks (0) | Category: Biological News | Chemical Biology
August 13, 2014
Well, the Discovery Channel has Shark Week, and apparently I have Sulfur Week going on around here. Or maybe it's Scripps Week (or Angewandte Chemie week), because here's the other paper from the Sharpless and Fokin labs on their new sulfonyl fluoride/sulfate ester chemistry. This is the extension to polymers: if you take a scaffold that has two of the sulfonyl fluoride esters on it, and react that with another OTMS-bearing monomer, you get a rapid and clean polymerization to a polysulfate.
This is a structural class that has been only lightly investigated, because of synthetic difficulties, but it's now wide open. You don't often get to see a whole new area appear like this. It'll be interesting to see what properties these have as bulk materials, when spun into fibers, and so on. And since it's polymer chemistry, the only way to find these things out is to make them and see what you get. Right off, they look like more chemically resistant forms of polycarbonates, which would surely find some use, but there are probably many other uses waiting out there as well.
The broader point made by Sharpless in this paper and the previous one is that sulfates are under-used and under-explored as functional groups. I suspect that most organic chemists will have encountered only dimethyl sulfate in their careers, and that one is hardly representative of a whole universe of compounds. Biological molecules get sulfated around their edges in vivo, but I don't think that the disulfate esters are used biologically at all (anyone know of any examples?) There must be a good reason for that, but I certainly don't know what it is. (Frank Westheimer's classic "Why Nature Chose Phosphate" is, as always, a good read in this area, but I don't think he considers sulfates in that paper). A more recent overview of the phosphorylation landscape also doesn't mention sulfates as an alternative, either. Phosphates clearly won out in the early days of biochemistry, but I don't know if that was all due to better thermodynamics, or availability (or both).
But as for organic synthesis, we can deal with all sorts of energy barriers, so there's no reason for us not to get some use out of sulfates. We just have to learn what they can do.
+ TrackBacks (0) | Category: Chemical News
The Baran group has a good method out in Angewandte on preparing sulfinates. That's a class of compound that, until recently years, not too many people have cared about - partly because they're generally not a lot of fun to make. The sulfinate