Novartis’s Afinitor helps Pfizer’s Aromasin to Delay Breast Cancer
Sep27

Novartis’s Afinitor helps Pfizer’s Aromasin to Delay Breast Cancer

Looks like Afinitor (everolimus), a drug marketed by Novartis for various cancers, may soon have a new indication. Already approved for a variety of diseases – kidney cancer, pancreatic tumors, and organ rejection prevention – Afinitor shows new promise for breast cancer patients. Clinical data released Monday demonstrate marked improvement for hormone-resistant breast cancer patients when Afinitor, an mTOR inhibitor, is used in combination with the aromatase inhibitor Aromasin (exemestane). Patients receiving both drugs delayed disease progression an average of 7 months, versus 3 months for Aromasin alone. Standard therapy for breast cancer includes treatment with estrogen receptor antagonists, such as Aromasin and tamoxifen, which bind in the estrogen receptor pocket of cancer cells, slowing proliferation (see the excellent NCI website for more information on breast cancer treatment). Aromasin itself has a very similar structure to estrone (a natural body hormone that binds to estrogen receptors) except that it irreversibly modifies the receptor pocket upon binding, making Aromasin a so-called “covalent” or “suicide” inhibitor (see Lila Guterman’s article from Sept. 5, 2011 issue of C&EN for more on drugs that bind for keeps). Like Aromasin, Afinitor follows the trend of being structurally related to a natural binder of a key cancer target protein. mTOR (mammalian target of rapamycin), the protein target of Afinitor and related macrolides, was first discovered through binding studies using rapamycin, a polyketide natural product found in a soil bacterium from Easter Island (its Polynesian name is Rapa Nui, hence, rapamycin). Rapamycin also goes by the generic name sirolimus, of which so many analogues have been prepared that all go by the catch-all “limus drugs.” The attachment of a hydroxyethyl (CH2CH2OH) tail to rapamycin produces everolimus, which compared to sirolimus demonstrates better pharmacokinetic properties, including higher bioavailability (greater proportion of drug reaching target sites) and a shorter plasma half-life (meaning the drug doesn’t stick around as long, which can help curb toxicity or other side effects). Note: Please see Sally Church’s post on Pharma Strategy Blog for more info on mTOR pathway biology and coverage of ECCO 2011 conference information regarding...

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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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Amides: Humble But Useful
Sep15

Amides: Humble But Useful

A heartfelt thank-you to Chemjobber and See Arr Oh for helpful discussions! CENtral Science’s benevolent overlord, Rachel Pepling, has organized a blog carnival around the theme of “your favorite chemical reaction”. For the Haystack’s contribution, I thought it would be appropriate to write about a reaction medicinal chemists might find familiar. So I re-read See Arr Oh’s post about which types of reactions were really the most common in the med-chem toolkit. I decided on amide formation, which sits just about at the top of the list. I’m not sure it’s my favorite chemical reaction; I’ve got a special place in my heart for the Heck reaction (or Mizoroki-Heck reaction), though I’ve already blogged extensively about it. But every amide bond formation I ran in grad school worked. That’s justification enough for me! Amides are the chemical ties that bind amino acids together to form peptides and proteins. Amides also turn up in a variety of other small molecules that nature makes. So it’s not surprising that amides are frequently found in drugs. Take a look at University of Arizona chemist Jón T. Njarðarson’s poster of top brand name drugs and marvel at the amide-y goodness. Amide bond formation isn’t accomplished by a single, archetypical chemical reaction– far from it. I thought I’d provide a brief overview of some classic chemistry in this area and then move into a selection of modern-day additions to the amide-construction toolkit. At first glance, it looks like all that’s needed to make an amide is to combine a carboxylic acid and an amine. But to make those two components come together, chemists have had to grease the wheels a bit by activating the carboxylic acid. Converting the carboxylic acid into an acid chloride or acid anhydride are among the oldest of the old-school methods for this. In 1955, MIT chemist John C. Sheehan reported a different idea—use of a coupling reagent, dicyclohexylcarbodiimide (DCC). Classics in Total Synthesis notes that in its time, DCC was “an important advance in the state of the art for forming amide bonds.” In fact, Sheehan used it, along with the base potassium hydroxide, in the critical final step of the first total synthesis of penicillin– construction of the beta-lactam ring of the molecule. However, separation of byproducts from the desired amide can be a limitation of DCC, according to the Haystack’s intrepid guest blogger See Arr Oh. Today, “O-chemists have newer, sexier reagents,” See Arr Oh adds. Those reagents include N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC), a next-generation version of DCC that’s water soluble, and other classes of activating reagents including uronium and phosphonium reagents. John Pokorsi, a student in Karl...

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Difficult C. difficile Infections – New Drug, New Targets
Aug31

Difficult C. difficile Infections – New Drug, New Targets

Trust your gut . . . scientifically speaking.  From belly-button bacteria to classification of signature microflora (all the various microbes that populate the intestinal tract), it feels like recent popular “culture” grows best in a petri dish. Many scientists now classify humans as superorganisms, meaning our survival depends on a host of “good” internal bacteria that digest fiber, make vitamins, and help the immune system. But what happens when these good bacteria suddenly get wiped out by a non-selective antibiotic? This sets the stage for a Clostridium difficile intestinal conquest. Simple contact transmits this bacterium between patients in hospitals, causing antibiotic-assisted diarrhea, bloating, and potential colitis. When a patient is treated with a broad-spectrum antibiotic, C. difficile survive by forming spores with tough outer coats, only to thrive again when there are few other bugs in the gut with which to compete. Two new players have recently entered the fight against the difficult C. difficile: first, Optimer Pharmaceuticals’ new narrow-spectrum antibiotic for C. diff. treatment, Dificid (fidaxomicin), approved in May 2011. This antibiotic macrolide belongs to the tiacumicin class of natural products, members of which have been known since Abbott first isolated compounds from fermentation broths in 1987. Dificid specifically inhibits Clostridium RNA polymerase enzymes; without these enzymes, gene transcription halts, and the cells die. Clearing the infection is great, but wouldn’t it be nice to ease the intestinal pain while the drug takes hold? Researchers at UTMB-Galveston might have found a good target for drugs that could do just that. In the August advanced online publications at Nature Medicine, Tor C. Savidge at UTMB-Galveston reports on human metabolites that can inhibit C. difficile toxins TcdA and TcdB, the major agents behind painful antibiotic-assisted diarrhea.  S-nitroso-glutathione, a nitroso (NO)-conjugated version of glutathione found in stool samples of infected patients, can “pass off” its NO group to the sulfur of a specific cystine amino acid residue in the toxins, shutting down their activity. The authors point out that instead of active site binding, the normal mode of action for most enzyme inhibitors, this NO seems to inhibit the toxins via an allosteric site, meaning they bind somewhere else on the toxin but still impair its function. Potency for in vitro inhibition is still in the high micromolar range (43-57 µm), but the study may point the way to the development of more selective NO-transfer...

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The Right Kinase, Part II – Roche and Daiichi’s Vemurafenib Approved
Aug24

The Right Kinase, Part II – Roche and Daiichi’s Vemurafenib Approved

Last week, the FDA approved Zelboraf (vemurafenib), co-marketed by Roche and Daiichi Sankyo, for the treatment of melanoma characterized by genetic mutation BRAF V600E, which occurs in a subset of the overall patient population. Treatment of late-stage melanoma patients with Zelboraf increases their survival around five months longer than traditional chemotherapy. Cancer-stricken families believe this extra time justifies the $9400 / month price tag for the treatment, considering the dearth of treatments currently available for these near-terminal patients  (for a more detailed look into the people who brought vemurafenib to market, read Amy Harmon’s New York Times article series from 2010). Vemurafenib went from concept to approval in just six years, lightning-fast for pharma, which usually takes decades to bring a drug to market. So, what’s the secret behind its success? Vemurafenib, developed initially by San Francisco pharma company Plexxikon (acquired in 2011 by Daiichi Sankyo) shows all the hallmarks of rational drug design. Initial screening of a 20,000-member compound library against the ATP-binding site of 3 kinases (Pim-1, CSK, and p38) yielded a 7-azaindole lead structure. This approach, known as fragment-based lead discovery (FBLD) – the concept that a drug can be built up from a tiny piece as opposed to a high-potency binder –  may represent a first for the industry, as pointed out by Dan Erlanson of blog Practical Fragments. Further synthetic modification of this azaindole fragment, supported by computer binding studies, showed that a hydrophobic (nonpolar) pocket on the enzyme surface could best be filled by a difluoro-phenylsulfonamide group. Biochemical assays confirmed that a ketone linker (in place of the 3-aminophenyl group shown above) between the azaindole and the sulfonamide increased potency. Additionally, a 5-chloro residue on the azaindole eventually became a 4-chlorophenyl group; it’s unclear how this relatively non-polar group helps improve binding, since early active-site models suggest it faces out towards the watery cell cytoplasm. How is Zelboraf halting melanoma growth? It all comes down to kinase inhibition, a topic covered with both a story and a Haystack post here at C&EN last year. B-RAF, a common gene overexpressed in melanoma cells, produces a protein kinase that is selectively inhibited by Zelboraf. Once shut off, this pathway reinstates a “lost” negative feedback loop for the BRAF V600E tumor cells, resulting in a cascade failure of growth factors further down the line. Cell growth arrest or apoptosis (cell death) follows, but only for the targeted melanoma cells, with no effect on non-cancerous cells. In an interesting twist, a review published in July shows that inhibitors of Raf kinases (the family of kinases that includes the product of the B-RAF gene) can be developed for...

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Tweaking A Workhorse Anesthetic
Aug22

Tweaking A Workhorse Anesthetic

In this week’s issue of C&EN, I’ve written about the search for new anesthetic drugs, as well as the accompanying quest for a better understanding of how anesthetics work. Anesthesia is safer than it’s ever been because highly trained physicians and nurses can manage its complications. The drive to improve anesthetics is nowhere near as strong as it is for other drug classes such as oncology drugs, as Imperial College biophysicist Nick Franks told me. But that doesn’t mean the drugs in use are perfect. Take propofol, or 2,6-diisopropylphenol, which is marketed as Diprivan by AstraZeneca. It’s arguably the most commonly used injectable anesthetic for surgeries in developed nations. It even has a nickname around the operating room, “milk of amnesia”, because of its effects on memory, and because of the milky appearance the sparingly water soluble compound takes on in the oil-water emulsion needed to deliver it to the bloodstream. But propofol has side effects. Several firms have made adjustments to propofol or its formulation in order to address the limitations, and they’re finding out whether those chemical tweaks translate into benefits for patients. For example, researchers at PharmacoFore, a privately-held biopharmaceutical company in San Carlos, Calif., reasoned that small changes to propofol’s structure might cut down on the pain experienced when propofol is injected. Anesthesiologists often use a topical numbing agent such as lidocaine to alleviate this pain. Work from other researchers suggested that the low concentration of propofol in the aqueous phase of the oil-water emulsion acts directly on a receptor on the inside of blood vessel walls to cause pain, says Thomas E. Jenkins, PharmacoFore’s chief scientific officer. “Short and sweet, our strategy was to make propofol more lipophilic,” in order to further reduce the concentration of the drug in the aqueous phase, the portion thought to be responsible for the pain, Jenkins says. PharmacoFore’s chemists also tried to leverage the concept that a single stereoisomer of a molecule can have pharmacological properties different from those of a mixture of stereoisomers. They investigated specific stereoisomers of 2,6-di-sec-butylphenol, which is more hydrophobic than propofol. The racemic version of this compound was similar enough to propofol that it hadn’t escaped chemists’ notice in the past- its anesthetic properties were evaluated in the 1980’s by the company that developed propofol itself (J. Med. Chem., DOI: 10.1021/jm00186a013). PharmacoFore evaluated a specific stereoisomer, (R, R)-2,6-di-sec-butylphenol (PF0713), in a phase I clinical study. In that study, PF0713 rapidly induced general anesthesia without injection pain and with minimal drop in blood pressure (blood pressure lowering is another known side effect of propofol). In addition, data from a preclinical study in rats combined...

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