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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HCV Followup: Anadys Acquired for Active Antiviral
Oct24

HCV Followup: Anadys Acquired for Active Antiviral

It’s been a busy six months for new Hepatitis C (HCV) meds: first, Merck and Vertex have their drugs approved in May, and then Pharmasset leaks PSI-7977 clinical data. Now, Anadys Pharmaceuticals has just announced Phase IIb results for its clinical candidate setrobuvir (ANA-598). The pill lowered virus levels to undetectable limits in 78% of patients after 12 weeks of combination treatment with either ribavirin or pegylated interferon. Anadys notes only one major side effect, a rash occurring in 1/3 of the ‘598-treated patients. The therapy targets patients in tough-to-treat HCV genotype 1 (gen1), unlike PSI-7977, which targets gen2 and gen3. The data seems to have convinced Roche, which acquired Anadys last Monday in all-cash deal analysts say represented a 260% premium over Anadys’s Friday stock closing price. Roche, no stranger to the HCV battle, hopes to integrate setrobuvir into a potential oral drug cocktail with its current suite of polymerase and protease inhibitors. Setrobuvir interacts with N5SB polymerase at the allosteric “palm” binding site, located in the center of the baseball-mitt shaped enzyme. The drug’s sulfur-nitrogen heterocycle – a benzothiadiazine – is the key to virus inhibition; Anadys has installed the motif in all their HCV inhibitors, going back to their 2005 patents. Chemists have known about the virus-targeting properties of this heterocycle for a while, but most derivatives have been culled in pre-clinical testing (see J. Antimicrob. Chemoth. 2004, 54, 14-16 for a brief review). Interestingly, chemists initially prepared benzodiathiazines, such as those in Merck’s chlorothiazide (c. 1957, according to the Merck Index), as diuretics, which found use in diabetic treatment. Over the next 40 years, modified medicines treated conditions ranging from epilepsy and cognitive therapy to hypertension and transcriptase regulation. Tweaked benzodiathiazines first showed anti-HIV and anti-CMV activity in the mid-1990s. One final advantageous wrinkle in this structure: unlike PSI-7977, setrobuvir is not nucleoside-derived. This feature changes its binding behavior, pharmacokinetics, and even its intellectual property strategies, since many current antiviral therapies mimic the nucleosides found in RNA and DNA chains....

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Two HCV Meds are Better than One for Pharmasset
Oct05

Two HCV Meds are Better than One for Pharmasset

An announcement hinting at the possibility of an all-oral hepatitis C treatment had researchers abuzz last week. Pharmasset, a Princeton, NJ company specializing in antiviral discovery, alluded to upcoming conference data that suggested a combination of ribavirin (a generic antiviral) and Pharmasset's experimental pill PSI-7977 lowered viral counts to near-undetectable levels in a ten-patient trial (kudos to Adam Feuerstein of The Street for initial reports. . . here at The Haystack, editor Lisa Jarvis has also tracked HCV drug development for some time now). Hepatitis C virus (HCV) is a chronic liver virus with an estimated 180 million infected worldwide. Two relatively new extermination options are available: Merck’s Victrelis (boceprevir) and Vertex’s Incivek (telaprevir), approved by the FDA ten days apart last year. Unfortunately, though both drugs are administered orally, each requires co-administration of injected interferon, which can cause severe fatigue and flu-like symptoms. Both oral drugs inhibit the same enzyme: the NS3 protease, which drags down a patient’s immunity and helps the virus to produce new copies of its proteins. In contrast, the ribavirin and PSI-7977 combination involves no injections, making it easier for patients to follow the appropriate medication schedule, and lessening side effects. The PSI compound also clips a different target: NS5B polymerase, an RNA enzyme that helps viral genetic replication. In addition, the PSI-7977 is “pan-genotypic,” meaning it inhibits several genetically different strains of HCV.  A 2010 article (J. Med. Chem. 2010, 53, 7202) details the full story of PSI-7977’s synthesis. Notice anything interesting? It’s really a nucleotide strapped on to a P-chiral prodrug, a “protected” substance the body later converts to the active drug species. This P-chiral motif is seen more often in asymmetric phosphine ligands (compounds that stick to metal catalysts during reactions to modify catalyst activity) than in drug development – often chemists install drug chirality at carbon or sulfur instead. The initial drug lead was actually a mixture of both phosphorus enantiomers (“Sp” and “Rp”), until process chemists realized they could selectively crystallize out the more potent “Sp” product. In the meantime, Pharmasset scientists haven’t stopped pushing their HCV portfolio forward: a recent paper (J. Org. Chem., 2011, 76, 3782) details a new lead: PSI-352938, a cyclic phosphate prodrug attached to a purine-fluororibose nucleotide warhead. The team credits this new prodrug design with a 10-100-fold increase in potency over the “naked” adenine drug for NS5B RNA polymerase inhibition. PSI-352938 recently completed a multiple ascending dose Phase I trial, in which a daily 200 mg dose brought HCV titres down below the detection limit in 5 of 8 patients.     ...

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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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Beating Trypanosomes
Aug01

Beating Trypanosomes

Above: Triatoma sanguisuga, a bug that carries Chagas disease. Photo by Jim Gathany / Arizona Department of Health Services Late last week, a group of researchers from the University of Ibadan in Nigeria published a paper (Parasitology Res., DOI: 10.1007/s00436-011-2516-z) on several herbal extracts that can kill the parasites that cause sleeping sickness. Unfortunately, important projects like that are few and far between. I'm almost done writing an article about drugs in development to treat sleeping sickness and Chagas disease, a pair of illnesses caused by a class of protozoans called trypanosomes. My story explains that the current treatments take several weeks, and the drugs have a wide variety of side effects ranging from rashes and headaches to neurological damage and death. One of my sources seemed to be overly confident that better treatments for these diseases are just around the corner based on the early performance of several compounds that are in clinical trials.  I'm not convinced. Not long ago, a compound codenamed DB-289 entered Phase III trials for sleeping sickness. Everything seemed to be going well. And then, suddenly, the trial was halted due to safety concerns. A handful of promising new drugs are making their way through clinical trials, and a few academic labs are looking for new compounds that can kill trypanosomes. Here is a roundup of some of those substances: Phthalazines A recent improvement upon the series of phthalazines developed by Manuel Sanchez-Moreno, Fernando Gomez-Contreras, and their colleagues in Granada, Spain. Very early stage, Chagas disease DDD85646 Identified by an academic library screening project, this compound inhibits N-myristoyltransferase in the trypanosomes that cause sleeping sickness. Preclinical, sleeping sickness SCYX-7158 An oxaborole similar to the ones developed by Anacor pharmaceuticals, a company that is testing boron-based drugs for a wide variety of antimicrobial applications. Late stage preclinical, sleeping sickness. K777 An inhibitor of the protease Cruzain, developed at UCSF, it may enter human trials within a year. Late stage preclinical, Chagas disease Posaconazole Already on the market as an antifungal drug, it kills T. cruzi in vitro tests. Preclinical, Chagas Fexinidazole Developed by Hoechst and shelved, DNDi resurrected this broad-spectrum agent. Phase I, sleeping sickness. E-1224 Eisai developed this azole prodrug as an antifungal agent. It is formulated as a monolysine salt. Phase II, Chagas disease DB-289 Proved effective, but trials were halted after participants showed signs of liver toxicity and renal insufficiency. Phase III, sleeping sickness Sleeping Sickness Drug Targets Pteridine Reductase, N-myristoyltransferase, Trypanosome alternative oxidase, BILBO1, glycosylphosphatidylinositol membrane anchors Chagas Disease Drug Targets Lanosterol 14α-Demethylase, Superoxide Dismutase, cytochrome P450 sterol 14-demethylase, Cruzain Here are some great sources of further information. All about diagnostics...

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Front-line Antibiotics To Fight E. Coli
Jun17

Front-line Antibiotics To Fight E. Coli

Guest blogger SeeArrOh comments on the limited chemical weapons available to treat E.coli and its Gram-negative brethren.  SeeArrOh is a Ph.D. chemist working in industry. Yesterday’s post at In the Pipeline asking what kind of translational research should be done garnered some remarks about the importance of developing antibiotics for Gram-negative bacteria. It’s a timely appeal, because this May an especially virulent strain of the Gram-negative microbe E. coli, named O104:H4, was discovered in Germany. As reported by the Robert Koch Institute, the German equivalent of the CDC, the outbreak has (to date) killed 35 people and sickened more than 3,200. This deadly strain produces Shiga toxins, which target the kidneys, causing hemolytic-uremic syndrome, a disease characterized by red blood cell death, low platelets, anemia, and  kidney failure. These outbreaks are not uncommon, as bacteria constantly evolve and adapt. So, when a superbug strikes, why don’t we have anything better to fight it with? Vaunted antibiotics vancomycin and the methicillin derivatives won’t hinder E. coli, since they are designed to stop a different type of microbe – Gram-positive, such as Staphylococcus or Pseudomonas.  E. coli's Gram-negative classification means that a fundamental difference in their cell walls lends them protection against certain antibiotics.  The fast reproduction rate of most bacteria, coupled with selection pressure from inhospitable environments (like new drugs), drives them to resistance even faster. Of course, we kill millions of E. coli all the time with common antibacterials: triclosan, a chlorophenol found in soaps and hand sanitizers, inhibits fatty-acid biosynthesis in both bacterial subtypes. Neosporin, familiar to many a scraped knee, contains two Gram-negative bactericides: neomycin sulfate and polymyxin B. To counter the tougher stuff, the front-line therapy against hospital-based E. coli infections has been the carbapenem antibiotics. These are extensions of the penicillin β-lactam motif, substituting sulfur for carbon, and are active against most strains of E. coli. Meropenem, first approved in 1996, was one of the first of this class, showing activity against abdominal and skin infections. Unlike penicillin, most carbapenems don’t reach the bloodstream efficiently when they are taken orally, which can limit their application. Though carbapenems may be strong antibiotics, E. coli fights back: in 2008, a bacterial enzyme was identified in E. coli taken from a patient traveling from India to Sweden, which granted resistance to the carbapenems.  This enzyme, better known as NDM-1 (New Delhi metallo-beta-lactamase-1) has the power to cleave the β-lactam bond found in most penicillin-derived compounds, thus rendering them non-lethal to the bacterium. So far, the NDM-1 variant has been found in the US, Canada, Japan, Brazil, Afghanistan, Australia, the UK, and India. Thanks to horizontal gene transfer, where...

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