And that’s it, folks! Watch the April 22nd issue of C&EN for more on this session.

The new structure adds a new section of GPCR space amenable to computer modeling (big blue circle), a space which includes sought-after drug targets. Previously determined GPCR structures, which are all from the same family, are highlighted in small blue and red circles. Image courtesy Heptares

Largely because of that drug discovery relevance, however, Heptares is choosing to keep its structure somewhat close to the vest. Officials presented views of the structure, of a GPCR called Corticotropin Releasing Factor (CRF-1) receptor, at conferences on Friday and Monday. But Heptares CEO Malcolm Weir says his team has no immediate plans to publish the structure or to deposit coordinates into the repository known as the Protein Data Bank.

The structure, Weir says, is another success for Heptares’ GPCR stabilizing technology, StaR. The technique involves targeted mutations that help to trap a GPCR in a single biologically-relevant state. In the case of CRF-1, Weir says, the stabilized receptor is captured in the “off” state.

The structure itself, which is at a resolution of 3 Ångstroms, has the 7-helix membrane-spanning structure typical of GPCRs. However, CRF-1′s architecture is rather different from receptors in Family A, the only GPCR family for which X-ray structures had been available until now, Weir says. “The overall shape of the receptor looks different, the orientation of the helices looks different, and there are detailed differences within helices that are at analogous positions in Family A receptors,” he says. He notes that there are differences in helices 6 and 7, which undergo important motions during GPCR activation.

“This is an important breakthrough, although fine details of the structure and release of coordinates may still be some time away,” says Monash University’s Patrick Sexton, an expert in Family B GPCRs who was at Friday’s talk. The structure, he says, confirmed researchers’ expectations that the major differences in membrane-spanning helices between Family A and Family B receptors would occur on the extracellular side. “There was a very open and relatively deep extracellular binding pocket, with the receptor having a ‘V’ shaped appearance,” he says. This open pocket likely contributes to medicinal chemists’ difficulties obtaining high affinity small molecule ligands for Family B receptors, he suggests.

That open pocket might be involved in another Family B GPCR mystery, according to Roger Sunahara, also in attendance Friday, who studies GPCRs’ molecular mechanisms at the University of Michigan, Ann Arbor. All Family B GPCRs, including CRF-1, have a large domain at their amino-terminus that contains large portions of their ligand binding sites. That domain was not included in this structure, he says, but “it would appear that deleted globular N-terminal domain would fit quite nicely into the open pocket.”

The CRF-1 receptor is a drug target for depression and anxiety, but at least one CRF antagonist failed to show benefit compared to placebo in a clinical trial. Weir says the impact of the CRF-1 structure for drug discovery will not necessarily be in CRF-1 drug discovery per se, but in the ability to develop relevant computer models of related targets.

It hasn’t been possible to make accurate models of Family B receptors with Family A information, explains Ryan G. Coleman, a postdoctoral fellow at UCSF who develops GPCR models, but who was not in attendance at the talks. Quality models could streamline small molecule drug discovery for the entire family, he explains. Most of the natural ligands for Family B receptors are long peptides, which are notoriously tough to replace with small molecule drugs.

Experts like Coleman will have to wait for some time to learn about the structure for themselves, unless they happened to have a friend in the audience at Heptares’ talks. It’s not unheard of for there to be a gap of several months to two years between a structure’s announcement and publication.

“We’re delighted to have such an informative structure,” Weir says. “It’s very exciting.” He adds says Heptares is progressing toward a structure of the biggest fish in family B, GLP-1, in the “on” state.

It was a meal Captain James Cook would just as soon have forgotten. The fish, an unfamiliar species, seemed harmless enough. But after just a small taste of its liver, he and two shipmates regretted it.

“We were seized with an extraordinary weakness in all our limbs attended with a numness [sic]…We each of us took a Vomet and after that a Sweat which gave great relief. One of the pigs which had eat the entrails was found dead… When the Natives came on board and saw the fish hanging up, they immidiately [sic] gave us to understand it was by no means to be eat.”

Cook had a rather more dramatic introduction to the lethal chemical tetrodotoxin than I did. I learned about it from a lecture in a windowless room. (Yes, I’ve linked to the original slides, still online after eight years.) That presentation had plenty to make my ears perk up. Highly poisonous. No antidote. Still kills today, because pufferfish, one of the web of creatures that makes tetrodotoxin, gets carved into a delicacy called fugu, and sometimes those knives miss a little bit of the animal’s toxic innards.

We weren’t learning about tetrodotoxin because of its deadliness. Tetrodotoxin, to the organic chemist, is a case study. The lab where I earned my Ph.D. is in the business of making the toughest molecules it can. The lessons teams learned by forging tetrodotoxin from scratch, the idea goes, will be useful in other endeavors. Chemists for decades have argued about whether this is an appropriate way to train students, but suffice to say it’s still the way that most medicinal chemists in pharma get their start.

Tetrodotoxin is different things to different people. To biochemists and neurobiologists, tetrodotoxin, or TTX for short, is a tool for unraveling how pain works. Researchers today know that TTX binds to sodium channel proteins involved with pain pathways in the nervous system.

To those who study the cultures of Haiti, tetrodotoxin evokes something else entirely– the zombie of Haitian tradition.

In the 1980s, ethnobotanist Wade Davis fingered tetrodotoxin as a key ingredient in a powder witch doctors use in voodoo zombie-making rituals. His doctoral thesis, as well as his bestselling book the “The Serpent and the Rainbow”, about the topic eventually became the basis for a movie of the same name.

Davis’s results came under fire from the medical and scientific community. Another team’s measurements of tetrodotoxin levels in the powder detected amounts too low to have any relevant effects, though Davis and another set of researchers have countered that fluctuations in pH dramatically affect those levels.

Tetrodotoxin levels aside, “the main criticism of Wade’s hypothesis is that tetrodotoxin does not confer the long term fugue that would be necessary to keep someone in a wakeful but zombified state,” says Frank Swain, a science writer currently working on a book about zombies. Swain also points to clinical examinations of three purported zombies, where each was diagnosed with a mental illness. “It seems zombies are just normal people with learning difficulties, who become pawns in various feuds as one family accuses another zombifying their children,” Swain says.

Davis, today an explorer-in-residence at the National Geographic Society, defends his work, saying that examining zombies with a purely chemical lens ignores their cultural context. “The zombie definition in Haiti has nothing to do with the poison,” he says. “Of course tetrodotoxin cannot make a zombie, but it can make someone appear to be dead.” From there, the belief system takes over and makes tetrodotoxin “the obvious culprit,” he adds.

Whether or not you adhere to the Haitian belief system, tetrodotoxin is a chemical that’s not to be messed with. Yet somehow fugu emerged as a delicacy. Customers line up, as the BBC puts it, to “play Russian roulette at the dinner table”. Consuming fugu is a much bigger gamble than consuming a burger made with the infamous meat product “pink slime”. But it was the slime that got the outrage.

It all comes down to information and choice. According to economist Robin Hanson, America is much more paternalistic when it comes to regulating foods consumed by the poor and by children, presumably because people feel those groups are unable to obtain or act on the information they’d need to make informed food choices.

Preserved pufferfish at the Heard Natural Science Center, Fairview, Texas (Flickr/gurdonark)

Our relationship with toxic chemicals is complicated. It isn’t always Nick Kristof’s “Big Chem” that’s out to obscure dangers or cloud our judgement. Sometimes, it’s human nature. We know smoking’s bad for us, and we do it anyway. But we don’t always know what lurks in, for example, a trailer provided by FEMA. Painting chemicals as “evil” or “good” is too simplistic- it’s all about their doses and their context. Instead of op-eds “teaching nothing more than a generalized chemical anxiety”, as Deborah Blum eloquently wrote, the world would be better served by op-eds that call for better information on what chemicals’ danger thresholds are. It’s a nuanced mission, but I’d venture a paper of the New York Times’ caliber is up to it.

Read (TEDMED)

Andrew Read thinks evolution is the best lens for staring down the superbugs. He took the stage Thursday at TEDMED, where he warned, “we’re picking a fight with natural selection.”

“Picking a fight without Darwin is like going to the moon without Newton,” Read added. “We are in the dark ages when it comes to evolutionary management.”

Read, director of Penn State University’s Center for Infectious Disease Dynamics, sat down with me on Thursday and shared a few principles he thinks the scientific community should keep in mind in order to keep antibiotic resistance in check. Here are his five tips for would-be superbug slayers.

Get smart with the drugs you’ve already got.
“We can’t rely on a continual supply of new drugs,” Read said. Many firms have already exited antibiotic research, he notes. “You can see that the markets aren’t good enough right now to drive innovation,” since new antibiotics are precious and used only for patients’ most severe infections rather than being prescribed widely. Read says firms should continually evaluate dosing and combination strategies with established drugs in order to stave off resistance. “I’m not saying we shouldn’t discover new antimicrobials,” Read stressed. “In some situations, like malaria, it’s really critical. But we don’t want to put all our eggs in that basket.”

Learn from what works.
“I think magic bullets are the exception rather than the rule,” Read says. But researchers should focus on why wildly successful therapies were so. “Why was that pathogen unable to get around the smallpox vaccine? Why is chloroquine still working against some malarias in some parts of the world when it’s has failed miserably in others?” Read asked.

Make the right matches for combination therapies.
Read notes that some antimalarial drug combinations have consisted of drugs with markedly different half-lives. In effect, once the first drug has left the human body, all that’s left is the other drug, a monotherapy. “And that’s dangerous,” a breeding ground for resistance, Read cautions. “You want to be combining drugs that have similar half-lives.” Researchers should also think about whether their antibiotics become more lethal to microbes when used in combination, or less lethal, Read says. Evidence suggests that less lethal is better, he says. According to work from Roy Kishony’s lab at Harvard Medical School, if an antibiotic combo is less lethal, once resistance develops to one drug (call it drug A) in the pair, then drug B can kick in, stronger than before, to kill off microbes that remains.

Consider your consequences.
Approaches that tame pathogens’ toxins haven’t yet reached the market, but are an active area of research (Nature Rev. Microbiol., DOI: 10.1038/nrmicro1818). “From an evolutionary point of view, they are extraordinarily interesting drugs, but possibly quite dangerous,” Read says. Why? Well, “it could go one of two ways,” Read explains. “The bacterial might not bother with the toxin, which would be good. Or it could try to overproduce and overwhelm the new drug, which would be bad.”

Invest in evolution management.
Antibiotic drug development, like development of any new drug, is a long, expensive slog, and Read thinks some of the resources could use redirection. “We get this thing at the end that’s taken us 12 years and a gazillion bucks. How much money did we put into figuring out how to make the damn thing work for much longer- maybe one tiny grant?” he says. “The work’s only just begun when you’ve got the drug.”

Petsko (TEDMED)

Gregory Petsko knows why he came to TEDMED. “I’m looking for Al Gore,” he told me flat-out over lunch. Folks who know Petskoknow the former Brandeis University biochemistry department chair isn’t one to mince words. And he’s nailed the reason why an academic might want to look outside traditional conferences and soak up some of the TEDMED aura. He’s looking for a charismatic champion to take up a biomedical cause: in Petsko’s case, it’s support for research in Alzheimer’s disease.

Petsko and Reisa Sperling, director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, talked about Alzheimer’s at TEDMED on Wednesday. Both talks were cast as calls to action. Just consider the introduction Petsko got from TEDMED chair and Priceline.com founder Jay S. Walker: “This is a man who hears a bomb ticking.”

Alzheimer’s statistics are sobering and Petsko used them to dramatic effect. People who will reach 80 by the year 2050 have a 1 in 3 chance of developing the disease if nothing is done, he told the audience. “And yet I hear no clamor,” he said. “I hear no sense of urgency.”

Petsko shared some not-yet-published work with TEDMED’s audience. His team is looking at a less-trod path of Alzheimer’s biology– the role protein sorting defects might play in the development of the disease. Their focus is on a protein complex called the retromer, which Petsko likened to a truck driver, because its job is to sort and send proteins either to the golgi–the cell’s recycling center, or to the lysosome for snipping. For Alzheimer’s, the thought is that improper sorting can make the difference between normalcy and an accumulation of amyloid-beta, the protein thought to be a key player in developing the disease. Petsko told me that his collaborator, Scott Small of Columbia University Medical School, discovered that retromer played a role in Alzheimer’s (Neuron, DOI: 10.1016/j.neuron.2006.09.001).

Petsko's truck analogy (Courtesy of G. Petsko)

Retromer's role in Alzheimer's (Courtesy of G. Petsko)

Petsko’s team has developed small molecules that increase the level of active retromer complex in the cell. So far, their agents have been evaluated in cultured cells. Tests in mice are ongoing.

It’s important for the Alzheimer’s field to look beyond amyloid-beta, says Kevin Sweeney, a TEDMED attendee who teaches at the University of California, Berkeley’s Haas School of Business and is part of the Rosenberg Alzheimer’s Project, a nascent organization that supports alternative avenues in Alzheimer’s research. “For a while, at least, the Alzheimer’s space looks like so many of the [clinical] trials have pursued a relatively narrow range of theories,” he says. Even though those theories aren’t fully played out, “we still think it’s useful to start looking for other strands,” he says.

“We can look for more of the same. Or we can look for things that are different in fundamental ways,” he adds.

After Petsko spoke, Sperling set out to convince the audience that the timing of Alzheimer’s clinical trials leaves something to be desired, and that early detection is a strategy worth pursuing.

By the time a patient reaches the medically and scientifically agreed-upon standard for Alzheimer’s disease, they’ve already notched many years of brain degeneration, Sperling notes. “And this is the stage of disease where we’re doing our clinical trials,” she says. Even mild cognitive impairment, an intermediate stage on the way to Alzheimer’s, “may already by too late” for intervention, since 50 to 70% of nerve cells have been lost from key memory networks by that point, Sperling says.

Sperling (TEDMED)

Barbara Tate, a neurobiologist and Vice President at Satori Pharmaceuticals, a firm working to develop its own Alzheimer’s therapies, told C&EN that the agreed-upon clinical criteria for Alzheimer’s disease are blunt diagnostic tools. (Sperling is on Satori’s scientific advisory board).

“Spouses have diagnosed the disease a decade before” their loved one meets the criteria, Tate said. “We call it mild or moderate Alzheimer’s disease but there’s nothing mild about it.”

It’s expensive to run Alzheimer’s clinical trials in their current incarnations, Tate says. However, she notes, “it’s been hard to make an economic argument for treating earlier.”

Patients at the earliest stages of cognitive decline can often still work, and still care for themselves, so their burden on society isn’t anywhere near that of a more advanced Alzheimer’s patient. And any therapy that would be designed for such early-stage interventions would have to be both very safe and very cheap, something that’s not easy to accomplish, she adds.

As for the TEDMED calls for action on Alzheimer’s, Tate is concerned that “there’s starting to be an exhaustion” among the public, researchers, and investors alike.

“People get tired of failed clinical trials,” such as the high-profile failures of Dimebon and semagacestat in the Alzheimer’s realm. Specifics about why a drug failed “don’t resonate,” she says. “All people hear is that a drug failed.”

Though there might be more clinical trial failures to come, Tate says “the data to hold out for” will come from what’s called the A4 trial, or Anti-Amyloid Treatment in Asymptomatic AD, which Sperling co-leads. This trial is aimed at treating people who have several Alzheimer’s risk factors but who have not developed the full-blown disease. It complements the Dominantly Inherited Alzheimer Network (DIAN) trial, which is looking at patients who have a mutation that are certain to develop the disease.

No word on whether Petsko has met his Al Gore yet. But what’s both good and bad about TEDMED is that he’s far from only person there who’s looking.

UPDATED 3:15PM 4/12: corrected Petsko’s chair status and odds of person of 80 developing Alzheimer’s by 2050.

But the organizers of TEDMED made a very deliberate decision in opening this year’s conference with Francis Collins. This is the first year that the gathering of medical luminaries, artists, and design gurus (TED stands for Technology, Entertainment, Design) is taking place in Washington, DC, after moving from San Diego. It marks a philosophical shift for the organization, from TEDMED as idea incubator to TEDMED as inserting itself into the national conversation on health and medicine. What better way to do that then bringing in the head of the biggest biomedical funding agency?

Collins wants to compress the time it takes to get a drug development pipeline, and make the pipeline less leaky. This isn’t news to folks around the pharma blogosphere, including here at the Haystack, Ash at Curious Wavefunction and Derek Lowe, who’ve followed last year’s announcement of NIH’s venture for drug discovery, the National Center for Advancing Translational Sciences.

Folks have expressed some concerns about the concept, and its emphasis on the promise of gene-based drug discovery. But, as Derek noted, the fact of the matter is that everyone in drug discovery wants the things Collins wants, so there’s a measure of goodwill for the venture too.

Collins spent his time on the TEDMED stage emphasizing two things: drug repurposing and developing high-tech cellular solutions to supplement and replace often-imperfect animal models.

On the tech side, Collins showcased the Harvard-based Wyss Institute’s lung-on-a-chip, which combines tissue engineering and electronics to mimic the interface between the lung’s air sacs and capillaries (Science, DOI: 10.1126/science.1188302). He said that technologies like this suggest viable alternatives to animal testing are possible.

When New Scientist reported on the lung-on-a-chip in 2010, researchers praised it as a step in the right direction, but cautioned that immortalized cell lines, such as those on the chip, don’t neccesarily behave like primary cells from patients. Collins also noted that it might be possible to use such devices with patients’ own cells someday.

On the repurposing side, Collins cited an article on the topic in Nature Reviews Drug Discovery (DOI: 10.1038/nrd3473), and alluded to lonafarnib (SCH 66336), a farnesyltransferase inhibitor that was originally designed to be part of cancer-treatment cocktails. It didn’t pan out as a cancer drug, Collins said, but now clinical trials are underway to test whether the drug is effective at countering a rare mutation that causes Hutchinson-Guilford progeria, an ailment that leads to rapid aging in children. Collins shared the stage with 15-year-old Sam, a progeria patient.

Francis Collins (right) and Sam. (TEDMED)

To bridge the massive gap between ideas and applications in medicine “we need resources, we need new kinds of partnerships, and we need talent,” he told the audience.

In a conversation with reporters after his talk, Collins provided another repurposing story published last month– bexarotene, a retinoid X receptor agonist intended for lymphoma that was just shown to clear amyloid-beta and reverse cognitive deficits in a mouse model of Alzheimer’s (Science, DOI: 10.1126/science.1217697)

At that chat, I asked Collins how the repurposing effort and his call for talent squares with massive layoffs in industry and flat or declining funding.
“It would help if we had a strong foundation of support,” Collins said. He said his agency’s purchasing power has decreased 20% over the last 8 years.

Another reporter asked what was the main obstacle to getting repurposing become habit. “IP,” Collins said. He told reporters that a model intellectual property sharing agreement with pharmaceutical companies has been drafted. Asked if companies had signed on to it, Collins said “we’re working on it.”

UPDATED 3:30PM 4/12: Here’s the scoop on Cookie Monster, for Muppet devotee Robin:
he spoke later in the session with ultramarathoner Scott Jurek about nutrition.

1:30PM It’s half an hour before the start of the session and the big ballroom is still pretty empty. Expect that to change in short order.

2:30PM LX4211
Company: Lexicon Pharmaceuticals
Meant to treat: type 2 diabetes
Mode of action: dual inhibitor of sodium glucose transporters 1 and 2, which play key roles in glucose absorption in the gastrointestinal tract and kidney
Medicinal chemistry tidbits: this drug candidate had Lexicon’s chemists refamiliarizing themselves with carbohydrate chemistry. Most inhibitors of sodium glucose transporters incorporate D-glucose in some way. Lexicon’s chemists realized they could try something different– inhibitors based on the scaffold of L-xylose, a non-natural sugar. The team has already published a J. Med. Chem paper (2009, 52, 6201–6204) explaining that strategy. LX4211 is a methyl thioglycoside-the team went with a methyl thioglycoside because upping the size too far beyond a methyl lost activity at SGLT1.
Status in the pipeline: LX4211 is currently completing Phase IIb trials.

3:00PM
BMS-927711
Company: Bristol-Myers Squibb
Meant to treat: migraine
Mode of action: antagonist of the receptor for calcitonin gene-related peptide- increased levels of this peptide have been reported in cases of migraine
Medicinal chemistry tidbits: This team recently published an orally bioavailable CGRP inhibitor, BMS-846372 (ACS Med. Chem. Lett., DOI: 10.1021/ml300021s). However, BMS-846372 had limited aqueous solubility, something that might make its development challenging. To improve that solubility, the BMS team sought to add polar groups to their molecule, something that’s been tough to do with CGRP inhibitors historically. In the end, the team managed to add a primary amine to BMS-846372′s cycloheptane ring while maintaining CGRP activity, leading to BMS-927711.
Status in the pipeline: Phase II clinical trials
3:05 lots of questions from the audience for this talk! One questioner notes (as was noted in talk) that 4 CGRP inhibitors had gone before this drug in the clinic, and not made it through. Speaker notes that this candidate is more potent than others at CGRP (27 picomolar).

3:53 We’re a bit behind schedule but got plenty of good chemistry…
GSK2636771

Company: GlaxoSmithKline
Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial
Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta.
Medicinal chemistry tidbits: The GSK team seemed boxed in because in 3 out of 4 animals used in preclinical testing, promising drug candidates had high clearance. It turned out that a carbonyl group that they thought was critical for interacting with the back pocket of the PI3K-beta enzyme wasn’t so critical after all. When they realized they could replace the carbonyl with a variety of functional groups, GSK2636771 eventually emerged. GSK2636771B (shown) is the tris salt of GSK2636771.
Status in the pipeline: Phase I clinical trials
4:22
GS-9620
Company: Gilead Sciences
Meant to treat: chronic infection with hepatitis B and C viruses
Mode of action: agonist of Toll-like receptor 7, which recognizes RNA from viral sources
Medicinal chemistry tidbits: The team paid a lot of attention to particular sidechain in their drug candidates– they examined a range of pKa’s from the acidic side of the scale to the basic side, and learned that a basic amine was important for agonist activity.
Status in the pipeline: Phase Ib clinical trials

4:49

BMS-791325
Company: Bristol-Myers Squibb
Meant to treat: hepatitis C
Mode of action: inhibitor of viral NS5B replicase
Medicinal chemistry tidbits: This drug candidate is an allosteric inhibitor– early on in the program BMS researchers had evidence to suggest that allosteric inhibition of the replicase would be feasible, and would provide an alternative to the nucleoside analogs that constitute the vast majority of replicase inhibitors. The team started with fused indole lead structures which bound to the thumb site 1 allosteric site in the replicase (Bioorg. Med. Chem. Lett., DOI: 10.1016/j.bmcl.2011.03.067). Adding a morpholine amide enhanced potency, and adding substituents to it abrogated transactivation of the pregnane X receptor (PXR). Ultimately this group was replaced with a methylated piperazine, with substituents stitched together to give another ring. A cyclopropane adjusted the shape of the molecule to jibe with information gathered from an X-ray co-crystal structure.
Status in the pipeline: Phase II clinical trials

4:52 That’s it folks! Watch for additional coverage of these talks in an April issue of C&EN.

So how’d Das make a difference? About one and a half years into the search for a kinase inhibitor that might be able to treat chronic myelogenous leukemia, “we were hitting a wall,” Barrish, today vice-president of medicinal chemistry at BMS, recalls. “We couldn’t get past a certain level of potency.”

Early on, the team’s work suggested that a 4′-methyl thiazole was critical for potency. Replace the methyl with a hydrogen, and potency went out the window. But Das challenged that dogma, Barrish says. He thought the compound series had evolved to the point where it would be a good idea to go back and test those early assumptions. His hunch paid off– in the new, later kinase inhibitor series, it turned out that removing the methyl group from the thiazole actually boosted potency. Thanks in large part to that discovery, the team eventually was able to make kinase inhibitors with ten thousand fold higher activity.

Dasatinib (J. Med.Chem.)

Generic naming requirements are extensive, but the committees involved in the naming process are willing to use inventors’ names as long as they fit the criteria.
But sometimes, Barrish says, “there’s luck involved in who makes the final compound.” In the dasatinib story, though, it was clear that Das’s discoveries were the keys to success.

When dasatinib was in clinical trials and it came time to put forward a set of possible generic names for consideration, Barrish didn’t have to think too hard about who was most responsible for his team’s success. “It was very clear in my mind that it was Jag,” he says. So he added dasatinib to the list.

“I admit, it was one of those things you do and you kind of forget about it, thinking, ‘oh, they’ll pick something else’,” Barrish says. When dasatinib ended up being the name of choice, he says, it made the entire team feel good. “And obviously, Jag was quite pleased with it.”

The TAK-875 story is as much about the biology of the target as it is about the molecule itself. And it’s a story that owes much to the company’s willingness to delve into uncharted territory.

In the early 2000s, scientists knew GPR40 existed, but didn’t know what GPR40′s purpose was in the body. Plenty of proteins fit this description– they’re called “orphan receptors” in the industry parlance. Much of Takeda’s drug discovery strategy is based on figuring out what orphan receptors do.

In a 2003 paper in Nature (DOI: 10.1038/nature01478), Takeda laid out what it learned about GPR40. The receptor responds to a variety of long-chain fatty acids. In response to fatty acid binding, GPR40 activates and boosts insulin secretion from pancreatic beta cells.

GPR40 became a viable drug target for Takeda for several reasons. First, one of the hallmarks of type 2 diabetes is a reduction in insulin secretion from pancreatic beta cells, something GPR40 activation could help counter. Second, G-protein-coupled receptors are established drug targets– and GPR40 happens to be in the class of GPCRs for which researchers know the most about structure– the Class A, or rhodopsin-like, GPCRs. (Note: other GPR-type receptors are diabetes targets as well– C&EN contributing editor Aaron Rowe has written about Arena Pharmaceuticals’ activators of GPR119 as diabetes drug candidates.)

TAK-875 docked to a model of GPR40 (ACS Med. Chem. Lett.)

Takeda used structural knowledge to its advantage in the discovery of TAK-875 (ACS Med. Chem. Lett., DOI: 10.1021/ml1000855). Researchers were able to build a model of GPR40 based on its similarity to GPCRs of known structure, and dock potential drug candidates inside to see how well they could bind.

This is far from the only drug discovery story that has to do with “de-orphanizing” orphan receptors. In fact, as far back as 1997, pharmaceutical company researchers were writing about orphan receptors as a neglected drug discovery opportunity (Trends Pharmacol. Sci., DOI: 10.1016/S0165-6147(97)90676-3). And of course, just because researchers have “de-orphanized” a receptor doesn’t mean all of the complex biology is pinned down. Case in point: the PPAR receptors (J. Med. Chem., DOI: 10.1021/jm990554g). Despite these receptors’ promise as targets for obesity and diabetes, drugs designed to target them have tanked in development or had unexpected problems after arrival on the market (read: Avandia).

So as TAK-875 enters Phase III trials, the news might be about the drug candidate’s clinical performance, but you can be sure that Takeda’s researchers are still working hard to unravel as much of GPR40′s basic biology as they can behind the scenes.

Make sure to read David’s fantastic overview to learn about each post in the carnival. But I’ve made note of a few favorites here at The Haystack:

Plenty of drugs don’t behave inside the human body the way drugmakers would like. But chemists have a few tricks up their sleeves to remedy that problem. For drugs that don’t stick around in the bloodstream long enough to work properly, or have other metabolic issues, a common tactic is to make a prodrug– a masked version of an active pharmaceutical ingredient. Once a person takes a pill containing a prodrug, the body’s own biochemical machinery breaks the prodrug down to the active ingredient. One of the most common chemical features of a prodrug is an ester group, a group that should be familiar to college students who’ve taken organic chemistry. I enjoyed chemistry professor and science writer Rebecca Guenard’s post at Atomic-o-Licious, The Smell of It, about prepping the undergrad laboratory exercise in ester formation. Bonus points for reminding me of a vintage Tenderbutton post about the barnyard aroma of certain carboxylic acids. (User: tender P:button).

Medicinal chemistry isn’t just about putting potential drugs together. It’s also about understanding the biology behind disease so that chemists can design better drugs in the future. Shannon Morey’s post at Chembites about the Azide Alkyne Huisgen Cycloaddition evokes that aspect of drug discovery quite well. This most famous reaction with the alias “click chemistry” has been used to probe countless biochemical processes. Most notably, Carolyn Bertozzi’s group at UC Berkeley has used it to learn more about sugars on cell surfaces and the many interactions where they participate. As Morey points out, Christopher Walsh’s Harvard Medical School team has even used this cycloaddition in the search for new antibiotic peptides.

Finally, because I don’t trust a chemist who can’t cook, I direct your attention to Matt Hartings’s elegant post at Sciencegeist on the Maillard Reaction, the chemistry behind roasting and toasting all kinds of culinary delights.

Thanks to all who participated in the carnival. Watch for selected posts in an upcoming issue of Chemical & Engineering News!