Category → Academe
We’re almost at the end of National Chemistry week, folks, and the Haystack is finally kicking in to blogger SeeArrOh’s now rampant #ChemCoach carnival. The goal of any carnival is to get a lot of different bloggers to post on the same topic–in this case, to write about how they got to where they are today as a way of educating young chemists on their career options. Round-ups of the dozens of posts this week can be found here, here, and here. Since the science writing field has been well covered here and by our own Carmen Drahl, and because the Haystack is focused on all things pharma, I thought I’d enlist the help of someone with a much more illustrious career than my own. Without further ado, I give you some words of career wisdom from TB Alliance‘s chemistry guru Christopher Cooper:
What you do in a standard “work day.”
What kind of schooling / training / experience helped you get there?
How does chemistry inform your work?
Finally, a unique, interesting, or funny anecdote about your career*
As drug companies forge closer ties with academic researchers, the value of pharma-academia partnerships continues to be cause for much debate (see here, here, here, and here for more on that). We’ve watched the evolution of these collaborations with interest, and as part of our ongoing coverage, this week’s issue brings an in-depth look at the mechanics of Pfizer’s Centers for Therapeutic Innovation, its network of academic partners centered on hubs in San Francisco, New York, Boston, and San Diego.
But much of our focus has been on what drug companies can gain from deeper ties with academia. There’s another side to the coin: what the academic lab gains from teaming up with industry. While visiting Pfizer’s Boston CTI, I was glad to have a long chat with Harvard’s Lewis Cantley, known in cancer research circles for the discovery of the PI3K pathway, about why it made sense to link up with Pfizer.
Cantley has had many pharma partnerships, was a founder of Agios Pharmaceuticals, and has sat on the boards of other start-ups. As such, I was curious what made him want to turn to Pfizer for this particular project—developing a drug against a cancer target discovered in his lab–rather than go at it alone, or try to spin out another company.
Cantley conceded that his lab could have plugged away at the target for several years and eventually come up with something promising. But the target requires an antibody, and his lab is more experienced at discovering small molecules. Pfizer, meanwhile, could step in with expertise and technology that they otherwise would never have access to, significantly speeding up the drug discovery process.
Further, Pfizer made teaming up easy. “The legalities of conflict of interest issues and IP issues had all been addressed with negotiations between Harvard and Pfizer before they even solicited proposals,” Cantley says. “To me, this was huge.” He notes that past partnerships with industry have involved at least a year of negotiating before anyone gets down to doing business—or, as it may be, science.
Another positive was that working with Pfizer meant researchers in his lab could continue to be involved with the project. When Cantley became a founder of Agios, which focuses on developing drugs that interrupt cancer cell metabolism, he could no longer ethically allow students in his lab work on that aspect of the science. But under the Pfizer pact, post-docs can continue to explore the drug development as well as any basic biological questions that may arise.
Lastly, Cantley was attracted by the facility with which Pfizer and academic scientists could interact. As it turns out, Cantley’s labs are in the same building as Pfizer’s Boston CTI. “It’s literally two minutes to get from my lab to theirs,” he notes. The seamless exchange of reagents and technologies occurs at a “speed which just doesn’t happen with other industry collaborations,” he says.
Indeed, as the story discusses, Pfizer is banking on that proximity to enable good targets or lead molecules to be quickly moved from the bench to the bedside. The goal is to have three to four compounds in human trials in the next 18 months—a swift turnaround considering the first CTI, a partnership with UCSF and labs in San Francisco, was announced just two years ago.
When you think of reaction screening, what comes to mind? Most would say LC-MS, the pharma workhorse, which shows changes in molecular polarity, mass, and purity with a single injection. Some reactions provide conversion clues, like evolved light or heat. In rare cases, we can hook up an in-line NMR analysis – proton (1H) usually works best due to its high natural abundance (99.9%).
Please welcome a new screening technique: 13C NMR. How can that work, given the low, low natural abundance of ~1.1% Carbon-13?
Researchers at UT-Southwestern Medical Center have the answer: rig the system. Jamie Rogers and John MacMillan report in JACS ASAP 13C-labeled versions of several common drug fragments, which they use to screen new biocatalyzed reactions.
Biocatalysis = big business for the pharma world. The recent Codexis / Merck partnership for HCV drug boceprevir brought forth an enzyme capable of asymmetric amine oxidation. Directed evolution of an enzyme made sense here, since they knew their target structure, but what if we just want to see if microbes will alter our molecules?
Enter the labeled substrates: the researchers remark that they provide an “unbiased approach to biocatalysis discovery.” They’re not looking to
accelerate a certain reaction per se, but rather searching for any useful modifications using the 13C “detector” readout. One such labeled substrate, N-(13C)methylindole, shows proof-of-concept with their bacterial library, producing two different products (2-oxindole and 3-hydroxyindole) depending on the amount of oxygen dissolved in the broth. NMR autosamplers make reaction monitoring a snap, and in short order, the scientists show biotransformations of ten more indole substrates.
This paper scratches multiple itches for various chem disciplines. Tracking single peaks to test reactions feels spookily close to 31P monitoring of metal-ligand catalysis. Organickers, no strangers to medicinally-relevant indole natural products, now have another stir-and-forget oxidation method. Biochemists will no doubt wish to tinker with each bacterial strain to improve conversion or expand scope. The real question will be how easily we can incorporate 13C labels into aromatic rings and carbon chains, which would greatly increase the overall utility.
Not long ago, metastatic melanoma was considered a graveyard for clinical research. But last year brought a major breakthrough in treating skin cancer: the approval of Roche’s Zelboraf (vemurafenib), a small molecule that has proven highly effective at treating the roughly 50% of the patient population that carry the BRAFV600E mutation.
However, Zelboraf has limitations. Patients’ disease eventually becomes resistant to the drug and the lesions caused by the skin cancer tend to return after 6 to 9 months.
At the American Society of Clinical Oncology (ASCO) meeting earlier this month, the big two questions on cancer specialists’ minds were: what are the mechanisms of resistance and how can we develop strategies to overcome them?
An amazing thing about current melanoma research is that several physician-scientists involved in the clinical trials are also actively involved in translational research–this is sadly the exception rather than the rule, in oncology. But the connection between basic science and bedside has meant new targets are being identified and quickly tested in the clinic.
One potential target recently discovered was MEK, a kinase that sits along the same signaling pathway as BRAF. When BRAF activity is turned off by Zelboraf, cancer finds a way to compensate for the loss by exploiting other kinases in the pathway. Researchers think that by combining a BRAF inhibitor with a MEK inhibitor, the pathway might be more comprehensively shut down than by either alone.
Consequently, there was a tremendous amount of buzz around a melanoma trial that looked at combining a BRAF inhibitor, GSK2118436 (dabrafenib), and a MEK 1/2 inhibitor, GSK1120212 (trametinib). Previous studies have shown that given alone, dabrafenib could result in solid response rates of 59%; trametinib, meanwhile, produced a 25% response rate when given as a single agent. Continue reading →
The evolution of the model for academic-pharma collaboration has been a topic of much discussion as more companies try to tap into university talent for early-stage research (recent examples of collaborations can be found here and here). Industry observers question whether anything tangible will come out of the efforts (see here for a recent critique), believing the divergent missions and cultural differences of each organization inevitably sidelines these pacts.
Pfizer is making one of the more aggressive pushes through its Centers for Therapeutic Innovation. Under the CTI model, Pfizer has set up labs in research hotbeds like Boston and San Francisco, where, through partnerships with various academic institutions, its scientists work side-by-side with university scientists to discover new biologics-based drugs. This week at BIO, I sat down with Tony Coyle, CTI’s chief scientific officer, to talk about CTI’s progress. A more in-depth look at the CTI model will come in the pages of the magazine, but in the meantime, I wanted to share some facts and figures that came out of our chat:
Number of CTIs formed: Four (San Francisco, San Diego, New York, Boston)
Number of academic centers involved: 20
Number of Pfizer scientists across each of its dedicated labs: roughly 100 (Coyle says about 75% were hired from the outside, coming from biotech, academia, with a few from big pharma)
Number of proposals reviewed in the last year: 400
Percentage of proposals overlapping with internal Pfizer efforts: <5%
Number of proposals funded so far: 23
Number of therapeutic areas being studied: 4 (rare diseases, inflammation, cardiovascular disease, and oncology)
Facts and figures aside, Pfizer is trying to move as quickly as possible given the learning curve of teaming with academia. Coyle said he’s promised his bosses that by the third year of the effort, at least four drugs will be in human studies across multiple therapeutic areas. “We’re well on our way to identifying a number of candidates, and I have no doubt that in the next 18 months, we’ll be in our first patient studies,” he added.
Those numbers could change in 2013, when Pfizer potentially expands its CTI outside the U.S. “Ex-U.S is still our ambition,” Coyle says. “2012 has been a period of ‘lets build the group, get the programs and start executing on the pipeline.’ For 2013, we will be and are looking at opportunities ex-U.S., and have had some pretty good discussions to date externally.”
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. Continue reading →
You know you’re at an interesting conference when the director of the NIH starts off his presentation with a guitar duet, and shares a session with Cookie Monster.
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.
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.”
Virulent bacteria are growing increasingly resilient against our best antibiotics. Each day seems to bring a new story: MRSA outbreaks, resistant salmonella, or tough-to-treat tuberculosis. Just last week, World Health Organization director-general Dr. Margaret Chan delivered an address in Copenhagen, where she cautioned: “We are losing our first-line antimicrobials . . . in terms of replacement antibiotics, the pipeline is virtually dry. The cupboard is nearly bare.” (Click here for The Haystack’s past coverage of the development of new antibacterials).
Why have our drugs stopped working?
Recent research from St. Jude’s (Science, 2012, 1110) attempted to answer that question. Using X-ray crystallography, a technique used to see structures at the atomic level, the researchers were able to capture a critical moment when a drug binds to DHPS, its bacterial enzyme target. The scientists could then predict how bacteria evolve to dodge further biocidal bullets.
The antibacterial medicines caught in the act by the St. Jude’s researchers are the sulfa drugs (see right), former front-line treatments many doctors push to the bottom of treatment regimens, due to increasingly resistant bacterial strains. Researchers knew resistance had something to do with the drugs’ mechanism of action; sulfa drugs mimic the binding of PABA – para-aminobenzoic acid, a compound found in many sunscreens (Chemical Note: PABA occurs naturally as bacterial vitamin H1, and can also be found in yeast and plants. Chemists often borrow naturally-occurring compounds for industrial uses; two prominent examples are vanillin and Vitamin C).
Disruption of this PABA binding shuts down bacterial DNA replication, stopping reproduction. Before now, however, no one had succeeded in growing crystals of the active site that actually showed the drugs interacting with the enzymatic intermediate.
Let’s take one more step back: how does PABA attach itself? The enzyme we’re discussing, DHPS, catalyzes bond formation between PABA and intermediates known as pterins (see picture, left). Earlier researchers believed that this molecular hook-up operated by an SN2 mechanism, a reaction where the PABA kicks out a small piece of the pterin to form a new C-N bond. We chemists would say that SN2 means concerted bond formation, meaning that PABA would bind at the same time as the leaving group (OPPi), well, leaves.
Turns out that picture’s not quite right: it’s more SN1-like, which means that the pterin first forms a positively-charged, enzyme-stabilized species! As you can imagine, this is no small feat, since the reaction works at physiological pH, in water, which could hydrate the intermediate (but doesn’t). Nope – instead, this charged molecule sits around waiting for a PABA – or a sulfa drug – to bind to it. When PABA binds, the complex exits the enzyme, but when the drug binds, it locks up the active site.
So how do these models help us to understand resistance?
The group noticed something odd: sulfathiazole (STZ) and sulfamethoxazole (SMX), two standard sulfas, both bound in the normal PABA cavity of DHPS. Unlike PABA, however, they hang their heterocyclic rings “outside” the normal pocket. The researchers built upon earlier observations by another group (Proc. Natl. Acad. Sci. U.S.A., 2010, 20986), speculating that the resistance might not have to do with the active site at all: it’s the external region, where the heterocycle bumps into the protein. To cheat death, all the bacterium needs to do is mutate an amino acid from this “outside” region (nearby proline and phenylalanine residues, see picture), which shuts down drug binding.
Could we design better drugs based on this model? Sure, we could synthesize a complimentary heterocycle, one that binds to the “outside” of mutant
enzymes (more polar for certain mutations, less for others). Another option? Cut the drug down to size: sulfonilamide, the grandfather of the sulfa drugs, should fit almost as snugly in the cavity as PABA, which might function perfectly against resistant bugs.
On Monday, we highlighted outtakes from our interview with Michael Ehlers, Pfizer’s CSO for neuroscience research, for our story on the state of neuroscience R&D. Today, we wanted to offer a view from academia: Jeff Conn is head of the Vanderbilt Center for Neuroscience Drug Discovery, which in the past several years has generated a number of CNS drug candidates.
While Ehler is focused on the growing body of genetic information that could pave the way for new neuroscience targets, Conn’s lab is taking a somewhat different approach. By scouring the literature for evidence–in humans–of a molecule or target’s activity, the lab then sinks substantial resources into understanding the basic biology driving that activity and designing molecules to exploit it.
In depression, for example, R&D has been stalled by a lack of new targets. But Conn’s lab is intrigued by studies showing that ketamine, an animal tranquilizer (and club drug), swiftly and effectively reduces the symptoms of major depressive disorder. “When I talk to scientists at Vanderbilt, its an approach they’re using for their most refractory patients,” Conn says.
A laundry list of side effects makes wider use of ketamine improbable. As such, Conn’s lab is looking at ways to design molecules that produce the same kind of results on depression without the adverse effects.
Conn, a former Merck researcher, also discussed ways that discovery efforts inside academia can build a scientific case for CNS programs that pharma might otherwise overlook. Vanderbilt scientists spend “twice as much effort in basic science than for the drug discovery itself, and to me, that’s absolutely critical,” Conn says. When the team finds that molecules have different profiles in vitro, they spend a lot of time trying to understand how that will translate into adverse effects in vivo. “In pharma, you have to stay on such a narrow, direct path, that you have to ignore all that,” Conn says. In the academic lab, researchers take a longer, more methodical approach that entails optimizing many different molecules, then putting those in animals to understand what properties a final drug candidate needs to have.
That approach has enabled Vanderbilt scientists to tackle drug targets that have tripped up industry. “mGluR5 is a good example where, early on, we started seeing different properties of molecules in vitro,” he says. “Instead of putting blinders on and moving forward or ignoring it,” an avenue industry scientists are often forced to take, “we deliberately put a lot of effort into optimizing those properties.”
As a result, the Vanderbilt group and its collaborator, J&J, recently moved forward what Conn calls “very safe” schizophrenia drug candidates targeting mGlur5. “I don’t think we ever could have done that in my pharma days because its too far off the critical path,” he says.
Medicinal chemists strive to optimize molecules that fit snugly into their proposed targets. But in the quest for potency, we often overlook the local physics that govern drugs’ binding to these receptors. What if we could rationally predict which drugs bind well to their targets?
A new review, currently out on J. Med. Chem. ASAP, lays out all the computational backing behind this venture. Three computational chemists (David Huggins, Woody Sherman, and Bruce Tidor) break down five binding events from the point-of-view of the drug target: Shape Complementarity, Electrostatics, Protein Flexibility, Explicit Water Displacement, and Allosteric Modulation….whew!
Note: Before we dive into this article, let’s clarify a few terms computational drug-hunters use that bench chemists think of differently: ‘decoy’ – a test receptor used to perform virtual screens; ‘ligand’ – the drug docking into the protein; ‘affinity / selectivity’ – a balance of characteristics, or how tightly something binds vs. which proteins it binds to; ‘allosteric’ – binding of a drug molecule to a different site on an enzyme than the normal active site. Regular readers and fans of compu-centric chem blogs such as The Curious Wavefunction and Practical Fragments will feel right at home!
We’ll start at the top. Shape complementarity modeling uses small differences in a binding pocket, such as a methylene spacer in a residue (say, from a Val to Ile swap) to dial-in tighter binding between a target and its decoy. The authors point out that selectivity can often be enhanced by considering a drug that’s literally too big to fit into a related enzymatic cavity. They provide several other examples with a ROCK-1 or MAP kinase flavor, and consider software packages designed to dock drugs into the “biologically active” conformation of the protein.
Electrostatic considerations use polar surface maps, the “reds” and “blues” of a receptor’s electronic distribution, to show how
molecular contacts can help binding to overcome the desolvation penalty (the energy cost involved in moving water out and the drug molecule in). An extension of this basic tactic, charge optimization screening, can be used to test whole panels of drugs against dummy receptors to determine how mutations might influence drug binding.
Because target proteins move and shift constantly, protein flexibility, the ability of the protein to adapt to a binding event, is another factor worth considering. The authors point out that many kinases possess a “DFG loop” region that can shift and move to reveal a deeper binding cavity in the kinase, which can help when designing binders (for a collection of several receptors with notoriously shifty binding pockets – sialidase, MMPs, cholinesterase – see p. 534 of Teague’s NRDD review).
But these shifting proteins also swim in a sea of water and other cytoplasmic goodies. This means that drug designers, whether they like it or not, must account for explicit water molecules. The authors even suggest a sort of “on-off” switch for including the bound water molecules, but contend that more efforts should be directed to accurate modeling of water in these protein settings.
Finally, the authors weigh the effects of allosteric binding, the potential for a modeled molecule to be highly selective for a site apart from where the protein binds its native ligand. The authors consider the case of a PTP1B ligand that binds 20Å away from the normal active site, at the previously mentioned “DFG loop.” Since this binding hadn’t been seen for related phosphatases, it could then be used to control selectivity for PTP1B.
In each section, the authors provide examples of modeling studies that led to the design of a molecule. Two target classes recur often throughout the review: HIV protease inhibitors (saquinavir, lopinavir, darunavir) and COX-2 inhibitors (celecoxib), which have all been extensively modeled.
Two higher-level modeling problems are also introduced: the substrate-envelope hypothesis, which deals with rapidly mutating targets, and tailoring molecules to take rides in and out of the cell using influx and efflux pumps in the membrane. Since different cell types overexpress certain receptors, we can use this feature to our advantage. This strategy has been especially successful in the development of several cancer and CNS drugs.
Overall, the review feels quite thorough, though I suspect regular Haystack readers may experience the same learning curve I did when adapting to the field-specific language that permeates each section. Since pictures are worth a thousand words, I found that glancing through the docking graphics that accompany each section helped me gain a crucial foothold into the text.