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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Guest Post: The Chemistry of Acne Treatments- How Galderma’s Epiduo Gel Works
May20

Guest Post: The Chemistry of Acne Treatments- How Galderma’s Epiduo Gel Works

Staying blemish free this Friday date night? SeeArrOh guest posts about the chemistry that makes it possible. SeeArrOh is a Ph.D. chemist working in industry. Pharmaceutical marketing, like all advertising, is all about finding the right audience.  Targeting drugs to their desired demographic is, after all, a multi-billion dollar industry.  Thus, for erectile dysfunction, well-to-do 50-somethings ride horses or sit in bathtubs watching the sunset.  For smoking cessation, you’re in a bar or restaurant having a great time and chewing nicotine-enhanced gum.  So it should come as no surprise that the new acne medication Epiduo targets its desired demographic, teenagers, with catchy graphics, cool phrasing (“breakout cheerleaders”, anyone?), and even an iPhone app to track your treatment. The pharmaceutical company behind Epiduo, Galderma Laboratories, has left nothing to chance to attract the attention of flighty fifteen year olds.  The Napoleon Dynamite-style graphics evoke scribbling on the back of Mead college-rule notebooks, and suggest that pimples are caused by inky black spirals under your skin.  So what did I think was so cool about Galderma’s otherwise predictable ads?  The actual structures of the two major drug components in Epiduo, adapalene and dibenzoyl peroxide, are prominently featured in bright colors flanking a unicorn, some stars, and a tentacle (more doodles).  I recall learning the structure of DNA and amino acids in eighth-grade biology, so perhaps it’s not too unbelievable that budding young chemists might want to know what’s in their face creams.  Dibenzoyl peroxide is no stranger to organic and medicinal chemists: it’s one of our favorite radical initiators.  Perhaps best known as a promoter of radical bromination (making carbon-bromine bonds under moderate heat) and to initiate polymerizations, it’s used here to cause oxidative damage to bacteria found in acne lesions.  The peroxide breaks down in tissue to form oxygen and benzoic acid, and this combination can both kill cells and cause unwanted skin bleaching, a known side-effect of acne medication.  Adapalene, on the other hand, is a black box, as its exact mechanism of action is unknown.  It belongs to a chemical class known as the retinoids, compounds made to mimic the structure of­ Vitamin A, also known as retinol.  Vitamin A itself is thought to improve skin condition by reducing oily secretions, lessening inflammation, and reducing bacteria in skin ducts.  Whereas previous retinoids were synthesized to mimic the conjugated tail of retinol, newer-generation retinoids such as adapalene and tazarotene bear the telltale mark of the medicinal chemist: adamantyl anisoles (adapalene) and acetylenic pyridines (tazarotene) tend not to be in Nature’s usual toolbox.  Like most potent drugs, Epiduo and tazarotene are prescription-only. However, some topical treatments are natural products used for other...

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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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