Haystack 2011 Year-in-Review
Jan03

Haystack 2011 Year-in-Review

Well, 2011 is in the books, and we here at The Haystack felt nostalgic for all the great chemistry coverage over this past year, both here and farther afield. Let’s hit the high points: 1. HCV Takes Off – New treatments for Hepatitis C have really gained momentum. An amazing race has broken out to bring orally available, non-interferon therapies to market. In October, we saw Roche acquire Anadys for setrobuvir, and then watched Pharmasset’s success with PSI-7977 prompt Gilead’s $11 billion November buyout.  And both these deals came hot on the heels of Merck and Vertex each garnering FDA approval for Victrelis and Incivek, respectively, late last spring. 2. Employment Outlook: Mixed – The Haystack brought bad employment tidings a few times in 2011, as Lisa reported. The “patent cliff” faced by blockbuster drugs, combined with relatively sparse pharma pipelines, had companies tightening their belts more than normal. Traffic also increased for Chemjobber Daily Pump Trap updates, which cover current job openings for chemists of all stripes. The highlight, though, might be his Layoff Project.  He collects oral histories from those who’ve lost their jobs over the past few years due to the pervasive recession and (slowly) recovering US economy.. The result is a touching, direct, and sometimes painful collection of stories from scientists trying to reconstruct their careers, enduring salary cuts, moves, and emotional battles just to get back to work. 3. For Cancer, Targeted Therapies – It’s also been quite a year for targeted cancer drugs. A small subset of myeloma patients (those with a rare mutation) gained hope from vemurafenib approval. This molecule, developed initially by Plexxikon and later by Roche / Daiichi Sankyo, represents the first success of fragment-based lead discovery, where a chunk of the core structure is built up into a drug with help from computer screening.From Ariad’s promising  ponatinib P2 data for chronic myeloid leukemia, to Novartis’s Afinitor working in combination with aromasin to combat resistant breast cancer. Lisa became ‘xcited for Xalkori, a protein-driven lung cancer therapeutic from Pfizer. Researchers at Stanford Medical School used GLUT1 inhibitors to starve renal carcinomas of precious glucose, Genentech pushed ahead MEK-P31K inhibitor combinations for resistant tumors, and Incyte’s new drug Jakifi (ruxolitinib), a Janus kinase inhibitor, gave hope to those suffering from the rare blood cancer myelofibrosis. 4. Sirtuins, and “Stuff I Won’t Work With  – Over at In the Pipeline, Derek continued to chase high-profile pharma stories. We wanted to especially mention his Sirtris / GSK coverage (we had touched on this issue in Dec 2010). He kept up with the “sirtuin saga” throughout 2011, from trouble with duplicating life extension in model organisms to the...

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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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