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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Mergers’ Latest Stint In The Hot Seat

Anyone who reads the comments at Derek Lowe’s In the Pipeline knows that drug company mergers are far from favorites among industry researchers. Mergers also took the heat at a pair of high-profile events this month. At this month’s ACS/Société de Chimie Industrielle panel discussion, former Pfizer Global R&D President John LaMattina laid the blame for ailing pharma pipelines largely on mergers. From today’s C&EN editorial by Rudy Baum: LaMattina’s comments focused on the negative impact of mergers and acquisitions on pharmaceutical R&D (Nature, DOI: 10.1038/nrd3514) calling them “a major factor in the decline in R&D productivity.” He pointed out that the Pharmaceutical Research & Manufacturers of America had 42 members in 1988, of which only 11 exist today as independent companies. While there are more than 11 current members of PhRMA, “the fact is , due to industry consolidation as well as some companies dropping their pharmaceutical R&D, there is far less competition in this industry than there was a decade ago.” “Lilly has announced that they are going to be growing organically, and not through M&A,” Baum says. At the Société event both LaMattina and fellow panelist Ron Breslow of Columbia wished the company well in this strategy, he adds. LaMattina confirms this, adding via Twitter “I would hope that Pharmas can succeed without the devastating effects of mergers.” It wasn’t just LaMattina and Breslow calling out mergers. Last Friday, at the Pharmaceutical Strategic Alliances Conference, Bristol Myers Squibb CEO Lamberto Andreotti said that avoiding mergers was part of what’s made his company successful. As tweeted by Pearl Freier, founder of advisory firm Cambridge BioPartners: PearlF: #PSA11 BMS transform, CEO credits continuity in R+D team working together for 7,8 years + No big mergers in 15 yrs, no disruptions You can read more about Andreotti’s remarks at...

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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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Drugs to Stop the “Brain-Eating Amoeba” N. fowleri
Aug25

Drugs to Stop the “Brain-Eating Amoeba” N. fowleri

Summer can be hot, and many people cool down by jumping in nearby lakes and rivers. However, that’s also where millions of microbes like to play: as reported by multiple news outlets, the third 2011 US death has now been attributed to what the popular press has dubbed “the brain-eating amoeba.” This “amoeba,” actually a protist called Naegleria fowleri, has been known to medicine since 1965. It belongs to a completely different biological branch from the true amoebas (I won’t go into all the biological background here, but Jennifer Frazier over at The Artful Amoeba has much more to say). This organism’s M.O. sounds like a cross between kuru (a brain-destroying prion disease)and flesh-eating bacteria. When a victim inhales freshwater containing N. fowleri, the organism attacks nasal membranes, working its way up towards the brain. Infected patients’ symptoms mimic those of encephalitis or meningitis, delaying proper drug treatment, while the protist quite literally consumes their nerve tissues. Sound gruesome? Well, so are the existing therapies to fight it – the CDC Naegleria fact sheet discloses no current best treatment. The infected often receive amphotericin B, an antifungal known to have toxicity issues, in combination with an antibiotic (minocycline, or azithromycin). These combination therapies may improve the overall infection survival rate, but targets for small-molecule inhibition have been sorely lacking. One promising biological lead to conquering N. fowleri does exist: the Nfa-1 gene. This gene produces proteins that impact the structure of the protist’s food cups, the organs used to digest tissue. A 2011 study indicated that chlorpromazine, an antipsychotic developed in the 1950s, inhibits Nfa-1 gene expression, and a 2008 test showed 75% survival of mice treated with chlorpromazine. Researchers hope this legacy drug can be further optimized to discover new N. fowleri...

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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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BMS-AstraZeneca Dapagliflozin Diabetes Drug Falls Short; Pfizer’s Answer on the Horizon?
Jul29

BMS-AstraZeneca Dapagliflozin Diabetes Drug Falls Short; Pfizer’s Answer on the Horizon?

As reported by Nature News and Forbes’ The Medicine Show  on July 20, dapagliflozin, a BMS-developed diabetes drug marketed with partner AstraZeneca, was given a “thumbs-down” by an FDA review panel on July 19. After the 9-6 final vote, panel members commented favorably on the drug’s new mechanism, but evidently felt that the safety profile could not be overlooked: the FDA committee meeting statement mentions increased risk of breast and bladder cancer, increased genital infections, and perhaps most seriously, potential for drug-induced liver injury (DILI). Dapagliflozin has been one of the rising stars of the new class of Sodium-Glucose cotransporter 2 (SGLT2) inhibitors for diabetes treatment, whose development roster includes Johnson & Johnson, Astellas, Boehringer Ingelheim, Roche, GSK, and Lexicon (Note: see Nat. Rev. Drug Disc. 2010, 551 for a full recap).  The excitement behind these drugs comes from a relatively new idea for diabetes treatment: inhibition of the SGLT2 enzyme stops the kidney from reabsorbing sugar, leading to excretion of the excess glucose in the urine, which in turn lowers blood sugar. Dapagliflozin, like most SGLT2 inhibitors, is a glucose molecule with a large aromatic group attached to the carbon atom in the spot chemists call the anomeric position. Such so-called C-glycosides are thought to have improved staying power in the bloodstream relative to O-glycosides (where the linkage point is at an oxygen atom, a more common scenario in sugars), since they are less susceptible to enzymatic breakdown. So, how do you improve these compounds? A paper Pfizer published last March (J. Med. Chem. 2011, 2952) may offer some hope.  Pfizer noted that some of the C-glycoside SGLT2 inhibitors gave a positive micronucleus test, indicating their potential to damage chromosomes. To work around this liability, their chemists  designed an analog of dapagliflozin where a second hydroxymethyl (CH2-OH) group is “tied” underneath the ring, forming a bicyclic compound that advantageously rigidifies the compound, increasing potency, while at the same time blocking a potential site of reactive metabolite formation (which might contribute to further DILI). The improved compound shows high potency for SGLT2 (~920 pm), a negative micronucleus test, and is now in Phase II  trials. Want to hear more? The lead author of Pfizer’s paper, Dr. Vincent Mascitti, will speak about the study as part of the Organic Division program at the ACS National Meeting in Denver – Sunday, August 28, 8:00 AM-8:30AM, Four Seasons...

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