A Last Summer Day Off
I'm going to be taking an extra day of vacation before the kids start back to school, so I'm adding to the Labor Day weekend today. Blogging will resume on Tuesday, unless something gigantic happens before then. If I can come up with something appropriate, maybe I'll put up a recipe! (Source: In the Pipeline)
Source: In the Pipeline - August 29, 2014 Category: Chemists Tags: Blog Housekeeping Source Type: blogs

The Early FDA
Here's a short video history of the FDA, courtesy of BioCentury TV. The early days, especially Harvey Wiley and the "Poison Squad", are truly wild and alarming by today's standards. But then, the products that were on the market back then were pretty alarming, too. . . (Source: In the Pipeline)
Source: In the Pipeline - August 28, 2014 Category: Chemists Tags: Regulatory Affairs Source Type: blogs

Drug Repurposing
A reader has sent along the question: "Have any repurposed drugs actually been approved for their new indication?" And initially, I thought, confidently but rather blankly, "Well, certainly, there's. . . and. . .hmm", but then the biggest example hit me: thalidomide. It was, infamously, a sedative and remedy for morning sickness in its original tragic incarnation, but came back into use first for leprosy and then for multiple myeloma. The discovery of its efficacy in leprosy, specifically erythema nodosum laprosum, was a complete and total accident, it should be noted - the story is told in the book Dark Remedy. A physicia...
Source: In the Pipeline - August 28, 2014 Category: Chemists Tags: Clinical Trials Source Type: blogs

The Smallest Drugs
Here is the updated version of the "smallest drugs" collection that I did the other day. Here are the criteria I used: the molecular weight cutoff was set, arbitrarily, at aspirin's 180. I excluded the inhaled anaesthetics, only allowing things that are oils or solids in their form of use. As a small-molecule organic chemist, I only allowed organic compounds - lithium and so on are for another category. And the hardest one was "Must be in current use across several countries". That's another arbitrary cutoff, but it excludes pemoline (176), for example, which has basically been removed from the market. It also gets rid of ...
Source: In the Pipeline - August 27, 2014 Category: Chemists Tags: Chemical News Source Type: blogs

Life Is Too Short For Some Journal Feeds
What scientific journals can you not be bothered to keep up with? I know, sometimes it's tempting to answer "all of them", but a well-informed chemist really should watch what comes out in the better ones. But how about the not-so-better ones? The "Life's too short" ones? Reading journals by RSS gives a person some perspective on signal-to-noise. One problem is that Elsevier's RSS feeds are sort of perpetually hosed. Are they working now? I haven't checked in a while, because I finally gave up on them. And that means that I don't regularly look at Tetrahedron Letters or Bioorganic and Medicinal Chemistry Letters, even th...
Source: In the Pipeline - August 27, 2014 Category: Chemists Tags: The Scientific Literature Source Type: blogs

A New Look at Phenotypic Screening
There have been several analyses that have suggested that phenotypic drug discovery was unusually effective in delivering "first in class" drugs. Now comes a reworking of that question, and these authors (Jörg Eder, Richard Sedrani, and Christian Wiesmann of Novartis) find plenty of room to question that conclusion. What they've done is to deliberately focus on the first-in-class drug approvals from 1999 to 2013, and take a detailed look at their origins. There have been 113 such drugs, and they find that 78 of them (45 small molecules and 33 biologics) come from target-based approaches, and 35 from "systems-based" appro...
Source: In the Pipeline - August 26, 2014 Category: Chemists Tags: Drug Assays Source Type: blogs

Small Molecules - Really, Really Small
Mentioning such a small compound as pirfenidone prompts me to put up the graphic shown below: these are the smallest commonly used drugs that I can think of. (OK, there's cocaine as a nasal anaesthetic - no, really - but that's where I draw the line at "commonly used". Nominations for ones that I've missed are welcome, and I'll update the list as needed. Note: four more have been added since the initial post, with more to come. This sort of thing really makes a chemist think, though - some of these compounds are very good indeed at what they do, and have been wildly successful. We need to keep an open mind about small mole...
Source: In the Pipeline - August 25, 2014 Category: Chemists Tags: Drug Industry History Source Type: blogs

InterMune Bought
It has been a bizarre ride for InterMune, its employees, and its investors. But now it ends with Roche buying them for $8.3 billion dollars, a sum that would have brought incredulous stares a few years ago. The deal makes sense for Roche, and it will provide investors a rationale for years as they buy into small biopharma companies - trying to pick the next InterMune, you know. (Source: In the Pipeline)
Source: In the Pipeline - August 25, 2014 Category: Chemists Tags: Business and Markets Source Type: blogs

Citable Garbage
Experimental and Clinical Cardiology used to be a reputable journal. Now it's a trash heap piled with crap. No, literally - the Ottawa Citizen newspaper has proof, thanks to reporter Tom Spears (who's an experienced hand at this). The journal was sold last year, and the new owners will publish absolutely anything you send them, as long as you send them $1200 to their bank account in the Turks and Caicos Islands. I wish I were making all that up, but that is exactly how it goes, offshore banking and all. Spears whipped together a gibberish cardiology paper by taking one about HIV and doing a find-and-replace to substitute ...
Source: In the Pipeline - August 25, 2014 Category: Chemists Tags: The Scientific Literature Source Type: blogs

The Palbociclib Saga: Or Why We Need a Lot of Drug Companies
Science has an article by journalist Ken Garber on palbociclib, the Pfizer CDK4 compound that came up here the other day when we were discussing their oncology portfolio. You can read up on the details of how the compound was put in the fridge for several years, only to finally emerge as one of the company's better prospects. The roots of the project go back to about 1995 at Parke-Davis: Because the many CDK family members are almost identical, “creating a truly selective CDK4 inhibitor was very difficult,” says former Parke-Davis biochemist Dave Fry, who co-chaired the project with chemist Peter Toogood. “A lot of ...
Source: In the Pipeline - August 22, 2014 Category: Chemists Tags: Cancer Source Type: blogs

Why Not Bromine?
So here's a question for the medicinal chemists: how come we don't like bromoaromatics so much? I know I don't, but I have trouble putting my finger on just why. I know that there's a ligand efficiency argument to be made against them - all that weight, for one atom - but there are times when a bromine seems to be just the thing. There certainly are such structures in marketed drugs. Some of the bad feelings around them might linger from the sense that it's sort of unnatural element, as opposed to chlorine, which in the form of chloride is everywhere in living systems. But bromide? Well, for what it's worth, there's a rep...
Source: In the Pipeline - August 21, 2014 Category: Chemists Tags: Drug Development Source Type: blogs

Fragonomics, Eh?
Edward Zartler ("Teddy Z" of the Practical Fragments blog) has a short piece in the latest ACS Medicinal Chemistry Letters on fragment-based drug discovery. He applies the term "fragonomics" to the field (more on this in a moment), and provides a really useful overview of how it should work. One of his big points is that fragment work isn't so much about using smaller-than-usual molecules, as it is using molecules that make only good interactions with the target.. It's just that smaller molecules are far more likely to achieve that - a larger one will have some really strong interactions, along with some things that actua...
Source: In the Pipeline - August 21, 2014 Category: Chemists Tags: Drug Assays Source Type: blogs

Amicus Fights Its Way Through in Fabry's
Perseverance is a critical variable in drug discovery. Too little of it, and you are absolutely guaranteed to fail - no drug has ever made it to market without trying the patience of everyone involved. Too much of it, and you are very nearly guaranteed to waste all your money: most drug development projects don't work, and eventually reach a point where no amount of time or money could make them work, either. Many are the efforts where leaders have gritted their teeth, redoubled their efforts, and led everyone further into the abyss. But sometimes these things come through, and that's what seems to have happened with Amic...
Source: In the Pipeline - August 20, 2014 Category: Chemists Tags: Clinical Trials Source Type: blogs

Did Pfizer Cut Back Some of Its Best Compounds?
John LaMattina has a look at Pfizer's oncology portfolio, and what their relentless budget-cutting has been doing to it. The company is taking some criticism for having outlicensed two compounds (tremelimumab to AstraZeneca and neratinib to Puma) which seem to be performing very well after Pfizer ditched them. Here's LaMattina (a former Pfizer R&D head, for those who don't know): Unfortunately, over 15 years of mergers and severe budget cuts, Pfizer has not been able to prosecute all of the compounds in its portfolio. Instead, it has had to make choices on which experimental medicines to keep and which to set aside. Howev...
Source: In the Pipeline - August 20, 2014 Category: Chemists Tags: Cancer Source Type: blogs

Don't Optimize Your Plasma Protein Binding
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 ...
Source: In the Pipeline - August 19, 2014 Category: Chemists Tags: Pharmacokinetics Source Type: blogs

Mouse Models of Inflammation: Wrong Or Not?
I wrote here about a study that suggested that mice are a poor model for human inflammation. That paper created quite a splash - many research groups had experienced problems in this area, and this work seemed to offer a compelling reason for why that should happen. Well, let the arguing commence, because now there's another paper out (also in PNAS) that analyzes the same data set and comes to the opposite conclusion. The authors of this new paper are specifically looking at the genes whose expression changed the most in both mice and humans, and they report a very high correlation. (The previous paper looked at the mouse...
Source: In the Pipeline - August 8, 2014 Category: Chemists Tags: Animal Testing Source Type: blogs

The Synthesis Machine
So I go away for a few days, and people are already planning to replace me (and my colleagues) with robots? Can't turn your back on anyone in this business. What that article is talking about is the long-term dream of a "synthesis machine", a device that would take whatever structure you fed into it and start in trying to make it. No such device exists - nothing even remotely close to it exists - but there's nothing impossible about it. A British project called Dial-a-Molecule is laying the groundwork. Led by Whitby, the £700,000 (US$1.2-million) project began in 2010 and currently runs until May 2015. So far, it has mos...
Source: In the Pipeline - August 7, 2014 Category: Chemists Tags: Chemical News Source Type: blogs

Summer Blogging Continues
Irregular summer blogging will continue until later this week - I'm on the road at the moment, and internet access is spotty. I'll be able to see my e-mail at some point, and occasionally clear out the spam that silts up the comments section, but otherwise I'll be hard to communicate with. (Source: In the Pipeline)
Source: In the Pipeline - August 4, 2014 Category: Chemists Tags: Blog Housekeeping Source Type: blogs

Animal Testing in the UK.
A reader sends along news that a minister at the UK's Home Office has made it his goal to completely eliminate animal testing in the country. Norman Baker has been a longtime activist on the issue of animal rights, and is now in a position to do something about it. Or is he? Reading the article, it seems to me to be one of these "Form a commission to study the proposals for the plan" things. The current proposal is to increase the publicly available details about what animals are being used for: In a statement, Mr Baker said: "The coalition government is committed to enhancing openness and transparency about the use of a...
Source: In the Pipeline - August 4, 2014 Category: Chemists Tags: Animal Testing Source Type: blogs

Amgen Cuts Hard
Amgen cuts over 2,500 jobs. Amgen completely shuts down its big facilities in Washington state and Colorado. Amgen's stock goes up nearly 7% in one day, adding about five (corrected late-night mistake) billion dollars in market cap. And there you have it. That's the industry. As this FierceBiotech piece says, Amgen's big shareholders have been unhappy with the way the company has been performing during the recent biotech bull market. This also puts the company in line with all the other big outfits who have been trimming staff and consolidating research sites in the past few years. It also puts them in line with all the c...
Source: In the Pipeline - July 31, 2014 Category: Chemists Tags: Business and Markets Source Type: blogs

Abandoned Pharma
It's not the most cheerful topic in the world, but NPR recently had an item on the decommissioned pharma research sites of New Jersey (of which there are many). Some of these are quite large, and correspondingly hard to unload onto anyone else. (This is, of course, a problem that is not unique to New Jersey, with plenty of ex-pharma sites around the US and the UK in particular falling into this category). I got to see this in an earlier and less severe form when I worked at Schering-Plough: the company's old Bloomfield site proved difficult to deal with in the early 1990s once everyone had moved out of it. No other compan...
Source: In the Pipeline - July 30, 2014 Category: Chemists Tags: Drug Industry History Source Type: blogs

Targacept Comes Up Empty, Yet Again
Targacept's attempt to salvage something by testing TC-5214 for overactive bladder has failed. John Carroll at FierceBiotech counts eight straight failed clinical trials from this company: a record? I don't see anyone beating that very easily, that's for sure. Nicotinic receptors have proven to be a very, very difficult field to work in, and I'm not sure that Targacept has anything left in their tank. (Source: In the Pipeline)
Source: In the Pipeline - July 28, 2014 Category: Chemists Tags: Business and Markets Source Type: blogs

Summer Blogging
I wanted to let everyone know that blogging will be irregular around here for the next week or so. I'll be taking some time off here and there, and while I'll surely get a few blog posts in, they won't show up at the usual times. (I started the whole time-off process over the weekend, with a trip to Stellafane, the big amateur astronomy gathering up in Vermont. Despite earlier weather forecasts, Saturday night was clear and dark, the best night skies I've seen in years. My wife and kids joined me (their first star party), and as we were getting pulled pork sandwiches from the food tent, my son looked around and said "Wow, ...
Source: In the Pipeline - July 28, 2014 Category: Chemists Tags: Blog Housekeeping Source Type: blogs

The Antibiotic Gap: It's All of the Above
Here's a business-section column at the New York Times on the problem of antibiotic drug discovery. To those of us following the industry, the problems of antibiotic drug discovery are big pieces of furniture that we've lived with all our lives; we hardly even notice if we bump into them again. You'd think that readers of the Times or other such outlets would have come across the topic a few times before, too, but there must always be a group for which it's new, no matter how many books and newspaper articles and magazine covers and TV segments are done on it. It's certainly important enough - there's no doubt that we real...
Source: In the Pipeline - July 25, 2014 Category: Chemists Tags: Infectious Diseases Source Type: blogs

Phenotypic Assays in Cancer Drug Discovery
The topic of phenotypic screening has come up around here many times, as indeed it comes up very often in drug discovery. Give your compounds to cells or to animals and look for the effect you want: what could be simpler? Well, a lot of things could, as anyone who's actually done this sort of screening will be glad to tell you, but done right, it's a very powerful technique. It's also true that a huge amount of industrial effort is going into cancer drug discovery, so you'd think that there would be a natural overlap between these: see if your compounds kill or slow cancer cells, or tumors in an animal, and you're on trac...
Source: In the Pipeline - July 24, 2014 Category: Chemists Tags: Cancer Source Type: blogs

Neratinib Comes Through For Puma
Yet another entry in the "Why do people keep investing in biopharma?" files. Take a look at the case of Puma Biotechnology. Their stock was as high as $140/share earlier in the year, and it gradually deflated to the high 50s/low 60s as time went on. But yesterday, after hours, they reported unexpectedly good Phase III results for neratinib in breast cancer, and as I write, they're at $228 or so, up about $167 per share. It's another HER2/EGFR tyrosine kinase inhibitor (like Tykerb/lapatinib in the small molecule space, although neratinib is an irreversible inhibitor) and would be targeted at patients who are now taking H...
Source: In the Pipeline - July 23, 2014 Category: Chemists Tags: Cancer Source Type: blogs

How Many Biopharma Employees Would Rather Be Working Somewhere Else?
How many people working in the biopharma industry would jump to another company if they could? According to this survey, it's just over half: well above the average set by other industry sectors. The usual reasons are cited, in part (pay, opportunity for advancement). But two factors that seemed unusually prominent in our industry were high stress levels and "difficult relations with supervisors and co-workers". I found that last one interesting, because (like all science and engineering fields) we do have a certain number of people in this business who can be described, as the old British music hall song has it, as "E's ...
Source: In the Pipeline - July 23, 2014 Category: Chemists Tags: Business and Markets Source Type: blogs

The Broad Gets $650 Million For Psychiatric Research
The Broad Institute seems to have gone through a bit of rough funding patch some months ago, but things are looking up: they've received a gift of $650 million to do basic research in psychiatric disorders. Believe it, that'll keep everyone busy, for sure. I enjoyed Eric Lander's characterization of much of the 1990s work on the genetic basis of mental illness as "pretty much completely useless", and I don't disagree one bit. His challenge, as he and the rest of the folks at the Broad well know, is to keep someone from being able to say that about them in the year 2034. CNS work is the ultimate black box, which makes a pe...
Source: In the Pipeline - July 22, 2014 Category: Chemists Tags: The Central Nervous System Source Type: blogs

Put Them in Cells and Find Out
So, when you put some diverse small molecules into cellular assays, how many proteins are they really hitting? You may know a primary target or two that they're likely to interact with, or (if you're doing phenotypic screening), you may not have any idea at all. But how many proteins (or other targets) are there that bind small molecules at all? This is a question that many people are interested in, but hard data to answer it are not easily obtained. There have been theoretical estimates via several techniques, but (understandably) not too much experimental evidence. Now comes this paper from Ben Cravatt's group, and it's...
Source: In the Pipeline - July 22, 2014 Category: Chemists Tags: Chemical Biology Source Type: blogs

The Hep C Field Gets Nastier By the Minute
What a mess there is in the hepatitis C world. Gilead is, famously, dominating the market with Sovaldi, whose price has set off all sorts of cost/benefit debates. The companies competing with them are scrambling to claim positions, and the Wall Street Journal says that AbbVie is really pulling out all the stops. Try this strategy on for size: In a lawsuit filed in February, AbbVie noted it patented the idea of combining two of Gilead's drugs—Sovaldi and an experimental drug called ledipasvir, which Gilead plans to combine into one treatment—and is therefore entitled to monetary damages if Gilead brings the combination...
Source: In the Pipeline - July 21, 2014 Category: Chemists Tags: Business and Markets Source Type: blogs

Allergan Twists and Turns
It's getting nasty over at Allergan. They're still trying to fight off a takeover attempt by Valeant, making the case that the company's R&D efforts are not a waste of money (which, only slightly simplified, is the Valeant position regarding every company they're taking over). But Allergan's had a lot of trouble getting one of their drugs (Semprana) through the FDA. Semprana is an inhaled version of the classic dihydroergotamine therapy for migraine, and had been rejected last year when it was still known as Levadex. The recent further delay isn't helping Allergan make its case, and Valeant is using this news to peel off...
Source: In the Pipeline - July 21, 2014 Category: Chemists Tags: Business and Markets Source Type: blogs

Chemistry Class For the "Food Babe"?
I found this article from the Charlotte Observer on the "Food Babe" (Vani Hari) very interesting. A "menu consultant" for Chick-Fil-A, is she? Who knew? I've come across a horribly long string of chemistry misapprehensions, mistakes, and blunders while looking at her site - she truly appears to know nothing whatsoever about chemistry, not that this would appear to bother her much. (Wavefunction has a good article on these). I noticed in the comments section of the newspaper's article that someone is apparently trying to crowdsource a fundraising drive to send her to some chemistry classes. I enjoy that idea very much, alt...
Source: In the Pipeline - July 18, 2014 Category: Chemists Tags: General Scientific News Source Type: blogs

Thalidomide, Bound to Its Target
There's a new report in the literature on the mechanism of thalidomide, so I thought I'd spend some time talking about the compound. Just mentioning the name to anyone familiar with its history is enough to bring on a shiver. The compound, administered as a sedative/morning sickness remedy to pregnant women in the 1950s and early 1960s, famously brought on a wave of severe birth defects. There's a lot of confusion about this event in the popular literature, though - some people don't even realize that the drug was never approved in the US, although this was a famous save by the (then much smaller) FDA and especially by Fra...
Source: In the Pipeline - July 18, 2014 Category: Chemists Tags: Biological News Source Type: blogs

TDP-43 and Alzheimer's
There are quite a few headlines today about a link between Alzheimer's and a protein called TDP-43. This is interesting stuff, but like everything else in the neurodegeneration field, it's going to be tough to unravel what's going on. This latest work, just presented at a conference in Copenhagen, found (in a large post mortem brain study of people with diagnosed Alzheimer's pathology) that aberrant forms of the protein seem to be strongly correlated with shrinkage of the hippocampus and accompanying memory loss. 80% of the cohort with normal TDP-43 (but still showing Alzheimer's histology) had cognitive impairment at dea...
Source: In the Pipeline - July 17, 2014 Category: Chemists Tags: Alzheimer ' s Disease Source Type: blogs

Google's Big Data Flu Flop
This article in Science finds that the real-world predictive power has been pretty unimpressive. And the reasons behind this failure are not hard to understand, nor were they hard to predict. Anyone who's ever worked with clinical trial data will see this one coming: The initial version of GFT was a particularly problematic marriage of big and small data. Essentially, the methodology was to find the best matches among 50 million search terms to fit 1152 data points. The odds of finding search terms that match the propensity of the flu but are structurally unrelated, and so do not predict the future, were quite high. GFT d...
Source: In the Pipeline - March 24, 2014 Category: Chemists Tags: Clinical Trials Source Type: blogs

Nitrogen Heterocycles Ahoy
Here's the sort of review that every working medicinal chemist will want to take a look at: Jeffrey Bode and graduate student Cam-Van T. Vo are looking at recent methods to prepare saturated nitrogen heterocycles. If you do drug discovery, odds are that you've worked with more piperidines, pyrrolidines, piperazines, morpholines, etc. than sticks can be shaken at. New ways to make substituted variations on these are always welcome, and it's good to see the latest work brought together into one place. There's still an awful lot to do in this area, though. As the review mentions, a great many methods rely on nitrogen protect...
Source: In the Pipeline - March 24, 2014 Category: Chemists Tags: Chemical News Source Type: blogs

Ezetimibe In the Marketplace
Several years ago, the Schering-Plough cholesterol absorption inhibitor (Zetia, ezetimibe) and its combination pill with simvastatin (Vytorin) were the subject of a lot of puzzled controversy. A clinical trial (ENHANCE) looking at arterial wall thickness in patients with familial hypercholesteremia had unexpectedly shown little or no benefit, although statins themselves had worked in this population. This led to plenty of (still unresolved) speculation about the drug's mechanism of action, whether it really was going to be of benefit to the wider patient population, what this meant for the surrogate endpoint of LDL lowerin...
Source: In the Pipeline - March 24, 2014 Category: Chemists Tags: Cardiovascular Disease Source Type: blogs

Dosing by Body Surface Area
We were talking about allometry around here the other day, which prompts me to mention this paper. It used the reports of resveratrol dosing in animals, crudely extrapolated to humans, to argue that the body surface area normalization (BSA) method was a superior technique for dose estimation across species. Over the years, though, the BSA method has taken some flak in the literature. It's most widely used in oncology, especially with cytotoxics, but there have been calls to move away from the practice, calling it a relic with little scientific foundation. (The rise of a very obese patient population has also led to contro...
Source: In the Pipeline - March 21, 2014 Category: Chemists Tags: Pharmacokinetics Source Type: blogs

Another Use for Xenon
An Australian reader sends this along from The Economist. Apparently xenon has been used for several years now to enhance athletic performance - who knew? Well, athletes, for one - here's an Australian cycling magazine talking about it, and Russian athletic federations have been recommending it for some time. That cycling article has a copy of a letter from the Russian Olympic committee, thanking a supplier for providing xenon to help prepare the team for the 2006 winter games in Turin. One's first impulse would be to snort and say "Snake oil!", but one's first impulse would probably be wrong. Xenon exposure is known to s...
Source: In the Pipeline - March 21, 2014 Category: Chemists Tags: Chemical News Source Type: blogs

For Some Folks, It's New Year's Day
A quick "eid-e shoma mubarak" to all those out there who are celebrating Norouz, the spring-equinox version of New Year's Day. My Iranian wife certainly is, and I will be pitching in by consuming large amounts of the home-made sweets that her mother has produced, and by frying a large quantity of fish for a big meal later on. For once, there's actually some blue sky and sunshine out there today (albeit with heaps of melting snow everywhere). But it sure beats a faceful of sleet, which has been the case several times in years past. (If you've ever seen the old W. C. Fields short, "The Fatal Glass of Beer", you'll get the id...
Source: In the Pipeline - March 20, 2014 Category: Chemists Tags: Blog Housekeeping Source Type: blogs

Small Molecule Chemistry's "Limited Utility"?
Over at LifeSciVC, guest blogger Jonathan Montagu talks about small molecules in drug discovery, and how we might move beyond them. Many of the themes he hits have come up around here, understandably - figuring why (and how) some huge molecules manage to have good PK properties, exploiting "natural-product-like" chemical space (again, if we can figure out a good way to do that), working with unusual mechanisms (allosteric sites, covalent inhibitors and probes), and so on. Well worth a read, even if he's more sanguine about structure-based drug discovery than I am. Most people are, come to think of it. His take is very sim...
Source: In the Pipeline - March 20, 2014 Category: Chemists Tags: Drug Industry History Source Type: blogs

Years Worth of the Stuff
This time last year I mentioned a particularly disturbing-looking compound, sold commercially as a so-called "selective inhibitor" of two deubiquitinase enzymes. Now, I have a fairly open mind about chemical structures, but that thing is horrible, and if it's really selective for just those two proteins, then I'm off to truck-driving school just like Mom always wanted. Here's an enlightening look through the literature at this whole class of compound, which has appeared again and again. The trail seems to go back to this 2001 paper in Biochemistry. By 2003, you see similar motifs showing up as putative anticancer agents i...
Source: In the Pipeline - March 20, 2014 Category: Chemists Tags: The Scientific Literature Source Type: blogs

Another Whack at the Stem Shortage Myth
Over at The Atlantic, Michael Teitelbaum has another crack at demolishing the "STEM shortage" myth. Looking over actual employment data, he finds: All have concluded that U.S. higher education produces far more science and engineering graduates annually than there are S&E job openings—the only disagreement is whether it is 100 percent or 200 percent more. Were there to be a genuine shortage at present, there would be evidence of employers raising wage offers to attract the scientists and engineers they want. But the evidence points in the other direction: Most studies report that real wages in many—but not all—scien...
Source: In the Pipeline - March 19, 2014 Category: Chemists Tags: Business and Markets Source Type: blogs

More Things Synthetic Chemists Hate
I enjoyed this post over at Synthetic Remarks on "Five things synthetic chemists hate". And I agree; I hate all of 'em, too. Allow me to add a few to the list: 1. The Mysterious Starting Material. How many times have you looked through an experimental section only to see a synthesis start cold, from a non-commercial compound whose preparation isn't given, or even referenced? One that doesn't seem to have any foundation anywhere else in the literature, either? I think that this is a bit more common in the older literature, but it shouldn't be happening anywhere. 2. It Works on Benzaldehyde; What More Do You Want? What abo...
Source: In the Pipeline - March 19, 2014 Category: Chemists Tags: Chemical News Source Type: blogs

Another DNA-Barcoded Program From GSK
Two more papers have emerged from GSK using their DNA-encoded library platform. I'm always interested to see how this might be working out. One paper is on compounds for the tuberculosis target InhA, and the other is aimed at a lymphocyte protein-protein target, LFA-1. (I've written about this sort of thing previously here, here, and here). Both of these have some interesting points - I'll cover the LFA-1 work in another post, though. InhA, for its part, is the target of the well-known tuberculosis drug isoniazid, and it has had (as you'd imagine) a good amount of attention over the years, especially since it's not the cl...
Source: In the Pipeline - March 18, 2014 Category: Chemists Tags: Infectious Diseases Source Type: blogs

Jailhouse Secrets They Don't Want You to Know About!
As I had hoped last year, scam artist Kevin Trudeau is indeed heading off for a ten-year sentence. I have searched, without success, for a photo of him wearing an orange jumpsuit and being bundled into a windowless prison van, but we'll just have to use our imaginations for that. Not to worry - a good steam cleaning, and the vehicle will be surely be fit to transport honest burglers again. Trudeau had been convicted of criminal contempt, for egregiously violating earlier court orders to stop ripping people off through his all-natural-cures informercial empire. Past entries here have detailed what the man is like, and if y...
Source: In the Pipeline - March 18, 2014 Category: Chemists Tags: Current Events Source Type: blogs

What If Total Syntheses Had Only 25 Steps to Work In?
In conclusion, this article tries to show how various strategies may be used to streamline and to shorten otherwise long synthetic routes to complex target molecules. The reader may get the impression that it pays very well to think intensively about cascade reactions, intramolecular cycloadditions, suitable starting materials and so on, instead of plunging into a brute-force and therefore mostly inefficient sequence. After all, there is an iron maxim: if a target cannot be reached within, say, 25 steps, it is better to drop it. For what you will get is a heroic synthesis, at best, but never an efficient one. A 25-step li...
Source: In the Pipeline - March 17, 2014 Category: Chemists Tags: Chemical News Source Type: blogs

Predicting What Group to Put On Next
Here's a new paper in J. Med. Chem. on software that tries to implement matched-molecular-pair type analysis. The goal is a recommendation - what R group should I put on next? Now, any such approach is going to have to deal with this paper from Abbott in 2008. In that one, an analysis of 84,000 compounds across 30 targets strongly suggested that most R-group replacements had, on average, very little effect on potency. That's not to say that they don't or can't affect binding, far from it - just that over a large series, those effects are pretty much a normal distribution centered on zero. There are also analyses that clai...
Source: In the Pipeline - March 17, 2014 Category: Chemists Tags: In Silico Source Type: blogs

Going After Poor Published Research
This should be interesting - John Ioannidis, scourge of poorly reproducible published results, is founding an institute at Stanford. The Economist has more: They will create a “journal watch” to monitor scientific publishers’ work and to shame laggards into better behaviour. And they will spread the message to policymakers, governments and other interested parties, in an effort to stop them making decisions on the basis of flaky studies. All this in the name of the centre’s nerdishly valiant mission statement: “Identifying and minimising persistent threats to medical-research quality.” It will be most interes...
Source: In the Pipeline - March 14, 2014 Category: Chemists Tags: The Scientific Literature Source Type: blogs

The Genetics of Bipolar Disorder: What A Tangle
Here's a brave attempt to look for genetic markers of bipolar disorder. The authors studied 388 Old Order Amish sufferers, doing thorough SNP analysis on the lot and total sequencing on fifty of them. There were many parent-child relationships in the set, which gave a chance for further discrimination. And the result: . . .despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implicatio...
Source: In the Pipeline - March 14, 2014 Category: Chemists Tags: The Central Nervous System Source Type: blogs