BARDA Bets on Boron to Bust Bacteria
Sep16

BARDA Bets on Boron to Bust Bacteria

GlaxoSmithKline recently announced a contract with the Biomedical Advanced Research and Development Authority (BARDA), a US government preparedness organization (Note: it’s not often pharma-relevant press releases come from the Public Health Emergency website!). The award guarantees GSK $38.5 million over 2 years towards development of GSK2251052, a molecule co-developed with Anacor Pharma a few years back, as a counter-bioterrorism agent. The full funding amount may later increase to $94 million, pending BARDA’s future option. The goal here is to develop “GSK ‘052”, as it’s nicknamed among med-chemists, into a new antibiotic against especially vicious and virulent Gram negative bacteria, such as the classic foes plague (Yersinia pestis) or anthrax (Bacillus anthracis). So what’s so special about this molecule? Usually, med-chemists “color” with the same atomic “crayons”: some carbon, sulfur, nitrogen, oxygen, and hydrogen, with a few halogens or transition metals every now and then (luckily, the golden age of mercury and arsenic therapies has largely passed on!). But seeing boron ensconced in a lead molecule rings alarm bells . . . you don’t usually see boron in pharmaceutical scaffolds! Look closely at GSK’052 (shown above): that’s a boron heterocycle there! Anacor, a company specializing in boron based lead compounds, first partnered with GSK in 2007 to develop novel benzoxaborole scaffolds. This isn’t the first company to try the boron approach to target proteins; Myogenics (which, after several acquisitions, became Millennium Pharma) first synthesized bortezomib, a boronic acid peptide, in 1995. Stephen Benkovic (a former Anacor scientific board member) and coworkers at Penn State first discovered Anacor’s early boron lead molecules in 2001, with a screening assay. The molecules bust bacteria by inhibiting  leucyl-tRNA synthetase, an enzyme that helps bacterial cells to correctly tag tRNA with the amino acid leucine. Compounds with cyclic boronic acids “stick” to one end of the tRNA, rendering the tRNA unable to cycle through the enzyme’s editing domain. As a result, mislabeled tRNAs pile up, eventually killing the bacterial cell. Inhibition of synthetase function turns out to be a useful mechanism to conquer all sorts of diseases.  Similar benzoxaborozoles to GSK ‘052 show activity against sleeping sickness (see Trypanosoma post by fellow Haystack contributor Aaron Rowe), malaria, and various...

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Acne-Fighting Boron Compounds, Anacor, and Medicis
Feb10

Acne-Fighting Boron Compounds, Anacor, and Medicis

Today biopharmaceutical company Anacor announced a partnership with Medicis to discover and develop small molecules to fight acne. Medicis brings its expertise in dermatology and aesthetics treatments to the table (it’s the company behind Juvederm, an injectable wrinkle filler). Meanwhile, Anacor’s mission is developing boron-containing drugs. Now, you don’t see boron in drugs very often. The first boron-containing drug- Millenium’s Velcade, for multiple myeloma- was approved less than ten years ago. Derek Lowe has mused about why medicinal chemists may have been reticent to check out boron compounds. But Anacor has built its company on boron chemistry. From its website: Boron based compounds have a unique geometry that allows them to have two distinct shapes, giving boron based drugs the ability to interact with biological targets in novel ways and can address targets not amenable to intervention by traditional carbon based compounds. So what’s this mean, exactly? It goes back to general chemistry. Boron has unusual bonding properties. Its outer electron shell, the most important one for chemical bonding, has only three electrons. If it makes three bonds to other atoms, it then has three pairs of electrons in its outer shell. That’s one pair short of what chemists typically consider stable. Still, these electron-deficient boron compounds tend to be pretty stable anyway. They have a flat shape to them chemists call trigonal planar. But these flat boron compounds have the potential to take in two more electrons. When they come into contact with, say, an oxygen or nitrogen-containing compound rich in electrons, the boron compound forms a new bond, called a dative or coordinate covalent bond. And the molecule changes its shape from flat (trigonal planar) to tetrahedral. Those are the two distinct shapes Anacor is talking about. And the company has made a few chemical tweaks to control this type of boron reactivity. What’s this have to do with acne? Well, the entire story’s not exactly clear. But we do know that enzymes often use electron rich oxygen, nitrogen, and sulfur motifs to do their business. And we know that Anacor’s antifungal in clinical trials, AN2690, gums up protein production with its distinctive bonding properties. We also know acne isn’t a completely new area for Anacor. At a 2006 American Academy of Dermatology Conference Anacor presented a compound designed to kill Propionibacterium acnes, a rod-shaped bacterium linked to zits. These bacteria normally dwell on human skin but clogged pores swell their ranks, and the chemicals they secrete (like propionic acid, hence their name) lead to the inflammation and irritation typical of acne. Antibacterials are already a common acne treatment. But the press release announcing the partnership doesn’t...

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Takeda Keeps On Truckin’ With Obesity Drug Research
Dec28

Takeda Keeps On Truckin’ With Obesity Drug Research

This year’s additions to the pile of setbacks in the obesity drug arena are enough to make anybody wonder whether big pharma companies will continue to invest in the field (was it already two years ago that Pfizer exited obesity research entirely?!). But news today of a pact between Takeda and Sanford-Burnham Medical Research Institute suggests the Japanese drug maker is in it for the long haul. Takeda’s agreement with Florida Hospital and Sanford-Burnham Medical Research Institute creates a partnership to evaluate potential new obesity drug targets. Today’s deal is the latest in a string of obesity-related investments for Takeda. Haystack readers may recall that Takeda is Orexigen’s partner for the development of Contrave, the weight-loss drug that is awaiting a decision from FDA in the wake of a thumbs-up from the agency’s advisory panel. The company also has a stake in peptides from Amylin Pharmaceuticals as potential obesity treatments, and it is conducting clinical development in Japan for Alizyme’s lipase blocker cetilistat, a next-generation pill to Xenical (orlistat), the drug sold over-the-counter as alli. Takeda’s interest in obesity makes sense given its strong history with type 2 diabetes drugs, a class with close ties to the obesity area. A quick look at Takeda’s pipeline is a whirlwind tour of diabetes drug targets, like glucokinase activators and dipeptidyl peptidase-4 inhibitors. The company has also discovered a protein, TGR5, that could be a target for drugs that mimic gastric bypass surgery‘s ability to control diabetes. And they are behind Actos, the well-known diabetes medication which shares its mechanism of action with Avandia. Unlike Avandia, Actos remains on the market, although FDA is currently investigating its safety. Will Takeda’s strategy pay off? Time will tell- beginning with FDA’s official decision on Contrave by the end of...

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Haystack 2010 Year-In-Review

This Friday, we’re looking back at 2010’s big news in pharma and biotech, both the good and the bad. Check out our picks and be sure to weigh in on what you think we missed. 1. Provenge Approved In April, Dendreon’s Provenge became the first approved cancer immunotherapy. Dendreon CEO Mitch Gold called it “the dawn of an entirely new era in medicine.” And while prostate cancer patients are excited for a new treatment option, the approval is perhaps most exciting for its potential to reignite interest in cancer immunotherapy research. There’s a lot of room for improving the approach—Provenge is, after all, expensive and highly individualized. Now that immunotherapy have been proven to work, there’s hope that the lessons learned in both its discovery and clinical development will aid scientists in inventing even better cancer vaccines. 2. Obesity Field Slims The obesity drug race played out in dramatic fashion in 2010, with three biotech companies-Vivus, Arena, and Orexigen, each making their case for its weight-loss medication before FDA. As of this writing, Orexigen’s drug Contrave seems to be on the surest footing to approval, but longtime obesity-drug watchers know that caution seems to rule the day at FDA, so nothing is a sure bet. Orexigen’s Contrave and Vivus’s Qnexa are both combinations of already-approved drugs, whereas Arena’s Lorqess is a completely new molecule. When C&EN covered the obesity race in 2009, it seemed that Lorqess (then going by the non-brand-name lorcaserin) had the cleanest safety profile, but Qnexa was best at helping patients lose weight. But FDA’s panels didn’t always play out the way folks expected. There were safety surprises- notably the worries about tumors that cropped up in rats on high doses of Lorqess, and the extensive questioning about birth defect risks from one of the ingredients in Vivus’ Qnexa. The fact that FDA’s panel voted favorably for Orexigen’s Contrave, a drug that’s thought to have some cardiovascular risks, generated discussion because FDA pulled Abbott’s Meridia, a diet drug with cardiovascular risks, from the market in October. The dust still hasn’t fully settled. Arena and Vivus received Complete Response Letters from FDA for Lorqess and Qnexa. Vivus has submitted additional documentation and a followup FDA meeting on Qnexa is happening in January. Also to come in January is the agency’s formal decision on Contrave. And if you’re interested in learning about the next wave of obesity drugs coming up in clinical trials, read this story in Nature News. 3. Sanofi & Genzyme: The Neverending Story Speaking of drama, Sanofi’s pursuit of Genzyme has been in the headlines for months now, and promises to stretch well into 2011. The...

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Pfizer Adds UCSF as First Partner in Academic Network

Pfizer has committed up to $85 million over five years to an expansive research agreement with the University of California, San Francisco, intended to speed the development of new biologic-based medications. More critically, the relationship with UCSF will be the first spoke in a network of academic collaborators, with Pfizer at the hub. Called the Center for Therapeutic Innovation, the goal is to bridge the gap between basic science and early clinical studies of potential drug candidates. Anthony Coyle, former head of respiratory, inflammation, and autoimmune disease research at MedImmune, will lead the network. Coyle says CTI will eventually be comprised of seven or eight partners: three or four in the U.S., one or two in Europe, and the remainder in Asia or Australia. Expect to see two more U.S.-based partners, one in NY and the other in Boston, added to the network by the end of the year, he adds. The creation of the CTI is Pfizer’s latest shake-up of the model for industry-academic collaborations. If you’ll recall, last spring, Pfizer caused a stir when it said it would give scientists from Washington University‘s School of Medicine access to data on 500 compounds that have gone through or are in some stage of clinical development. The hope is that fresh eyes with deep insights into the biology of disease and drug targets might lead to new uses for the compounds. See our recent cover story on the deal for much more detail on how that arrangement works. Ultimately, Pfizer hopes that by breaking down some of the barriers that have hindered an open exchange between industry and academia—the right to publish, ownership of intellectual property, shared profits on products, to name a few—it will be able to get new drugs to market faster. Coyle says the CTI will be solely focused on biologic-based drugs, mainly because he wants each center to be fairly autonomous and able to make decisions quickly. With the infrastructure required to develop small molecules, they would have had to rely on medicinal chemists “in distant locations,” and would run the risk of creating an “overburdened” project. The first step in the UCSF collaboration will be a trip by Coyle and other Pfizer executives to the campus in December to explain the program. Because Pfizer believes the projects will only work if scientists are working side-by-side, the company will set up new labs that can accommodate up to 40 scientists close to the UCSF campus. University scientists will have access not just to Pfizer’s drug development knowledge, but to its research tools—of particular note is that Pfizer is making its phage display libraries accessible to those...

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GSK Highlights Rare Diseases Approach

GlaxoSmithKline today outlined its strategy in rare diseases, while also unveiling its latest licensing deal in the area. Created in February, the rare diseases unit will focus on four therapeutic areas–metabolism, central nervous system and muscle disorders, immunoinflammation, and rare malignancies and hematology—and will initially chase treatments for 200 diseases. “We believe that focusing on 200 diseases is a good compromise between the enormity of the task and what we can really address with the team we have in place,” Marc Dunoyer, head of GlaxoSmithKline’s rare diseases unit said on a call with reporters this morning. Pursuing treatments for 200 diseases seems ambitious. After all, the rare diseases unit is comprised of just 30 people who work with scientists in GSK’s 38 discovery performance units as well as leverage outside opportunities. But Dunoyer pointed out that roughly 3,000  rare diseases are rooted in genetics, which provides natural starting points for drug discovery campaigns. Further, the company appears to be looking for deals that bring technologies that can be applied across a range of diseases. The company has already established a small network of partners with edgy drug discovery technology. Prior to the creation of the unit, GSK paid $25 million upfront for Prosensa’s PRO051, an RNA-based therapeutic now in Phase II trials for the treatment of Duchenne muscular dystrophy. GSK then bought the rights to a number of enzyme replacement therapies from JCR Pharmaceuticals. In March, GSK signed a broad pact worth up to $1.5 billion to use Isis Pharmaceuticals’ antisense technologies to develop therapies for rare diseases. Today, GSK announced a partnership with Italian charity Fondazione Telethon and research organization Fondazione San Raffaele for the development of gene therapies based on the patient’s own bone marrow. In exchange for $14 million upfront and the promise of milestones, GSK gains access to a gene therapy that has completed Phase I/II trials in ADA severe combined immune deficiency, more commonly known as “bubble boy disease,” which affects just 350 children worldwide. The organizations will use the stem cell technology to develop treatments for a variety of other rare diseases based on single-gene mutations. GSK isn’t the only drug company with a newfound interest in rare diseases. In December, Pfizer started a rare diseases unit, which recently set up an R&D group in Cambridge, Mass. Sanofi-Aventis has for months been trying to buy Genzyme in order to bolster its rare diseases portfolio. Novartis has also become interested in rare diseases as a foothold into larger...

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