TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay
Apr13

TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay

Researchers may like to think they’re pretty smart, but you could argue that bacteria have also got some bragging rights. Every day, microbes develop resistance to even the most powerful antibiotics scientists have developed. Andrew Read thinks evolution is the best lens for staring down the superbugs. He took the stage Thursday at TEDMED, where he warned, “we’re picking a fight with natural selection.” “Picking a fight without Darwin is like going to the moon without Newton,” Read added. “We are in the dark ages when it comes to evolutionary management.” Read, director of Penn State University’s Center for Infectious Disease Dynamics, sat down with me on Thursday and shared a few principles he thinks the scientific community should keep in mind in order to keep antibiotic resistance in check. Here are his five tips for would-be superbug slayers. Get smart with the drugs you’ve already got. “We can’t rely on a continual supply of new drugs,” Read said. Many firms have already exited antibiotic research, he notes. “You can see that the markets aren’t good enough right now to drive innovation,” since new antibiotics are precious and used only for patients’ most severe infections rather than being prescribed widely. Read says firms should continually evaluate dosing and combination strategies with established drugs in order to stave off resistance. “I’m not saying we shouldn’t discover new antimicrobials,” Read stressed. “In some situations, like malaria, it’s really critical. But we don’t want to put all our eggs in that basket.” Learn from what works. “I think magic bullets are the exception rather than the rule,” Read says. But researchers should focus on why wildly successful therapies were so. “Why was that pathogen unable to get around the smallpox vaccine? Why is chloroquine still working against some malarias in some parts of the world when it’s has failed miserably in others?” Read asked. Make the right matches for combination therapies. Read notes that some antimalarial drug combinations have consisted of drugs with markedly different half-lives. In effect, once the first drug has left the human body, all that’s left is the other drug, a monotherapy. “And that’s dangerous,” a breeding ground for resistance, Read cautions. “You want to be combining drugs that have similar half-lives.” Researchers should also think about whether their antibiotics become more lethal to microbes when used in combination, or less lethal, Read says. Evidence suggests that less lethal is better, he says. According to work from Roy Kishony’s lab at Harvard Medical School, if an antibiotic combo is less lethal, once resistance develops to one drug (call it drug A) in the pair, then drug B can...

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TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore
Apr12

TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore

Gregory Petsko knows why he came to TEDMED. “I’m looking for Al Gore,” he told me flat-out over lunch. Folks who know Petskoknow the former Brandeis University biochemistry department chair isn’t one to mince words. And he’s nailed the reason why an academic might want to look outside traditional conferences and soak up some of the TEDMED aura. He’s looking for a charismatic champion to take up a biomedical cause: in Petsko’s case, it’s support for research in Alzheimer’s disease. Petsko and Reisa Sperling, director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, talked about Alzheimer’s at TEDMED on Wednesday. Both talks were cast as calls to action. Just consider the introduction Petsko got from TEDMED chair and Priceline.com founder Jay S. Walker: “This is a man who hears a bomb ticking.” Alzheimer’s statistics are sobering and Petsko used them to dramatic effect. People who will reach 80 by the year 2050 have a 1 in 3 chance of developing the disease if nothing is done, he told the audience. “And yet I hear no clamor,” he said. “I hear no sense of urgency.” Petsko shared some not-yet-published work with TEDMED’s audience. His team is looking at a less-trod path of Alzheimer’s biology– the role protein sorting defects might play in the development of the disease. Their focus is on a protein complex called the retromer, which Petsko likened to a truck driver, because its job is to sort and send proteins either to the golgi–the cell’s recycling center, or to the lysosome for snipping. For Alzheimer’s, the thought is that improper sorting can make the difference between normalcy and an accumulation of amyloid-beta, the protein thought to be a key player in developing the disease. Petsko told me that his collaborator, Scott Small of Columbia University Medical School, discovered that retromer played a role in Alzheimer’s (Neuron, DOI: 10.1016/j.neuron.2006.09.001).   Petsko’s team has developed small molecules that increase the level of active retromer complex in the cell. So far, their agents have been evaluated in cultured cells. Tests in mice are ongoing. It’s important for the Alzheimer’s field to look beyond amyloid-beta, says Kevin Sweeney, a TEDMED attendee who teaches at the University of California, Berkeley’s Haas School of Business and is part of the Rosenberg Alzheimer’s Project, a nascent organization that supports alternative avenues in Alzheimer’s research. “For a while, at least, the Alzheimer’s space looks like so many of the [clinical] trials have pursued a relatively narrow range of theories,” he says. Even though those theories aren’t fully played out, “we still think it’s useful to start looking for other strands,”...

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Liveblogging First-Time Disclosures From #ACSSanDiego
Mar24

Liveblogging First-Time Disclosures From #ACSSanDiego

Watch this space on Sunday as I cover the public unveiling of five drug candidates’ structures. I’ll be liveblogging the “First Disclosures of Clinical Candidates” symposium at the San Diego ACS National Meeting, which runs from 2PM to 5PM Pacific. 1:30PM It’s half an hour before the start of the session and the big ballroom is still pretty empty. Expect that to change in short order. 2:30PM LX4211 Company: Lexicon Pharmaceuticals Meant to treat: type 2 diabetes Mode of action: dual inhibitor of sodium glucose transporters 1 and 2, which play key roles in glucose absorption in the gastrointestinal tract and kidney Medicinal chemistry tidbits: this drug candidate had Lexicon’s chemists refamiliarizing themselves with carbohydrate chemistry. Most inhibitors of sodium glucose transporters incorporate D-glucose in some way. Lexicon’s chemists realized they could try something different– inhibitors based on the scaffold of L-xylose, a non-natural sugar. The team has already published a J. Med. Chem paper (2009, 52, 6201–6204) explaining that strategy. LX4211 is a methyl thioglycoside-the team went with a methyl thioglycoside because upping the size too far beyond a methyl lost activity at SGLT1. Status in the pipeline: LX4211 is currently completing Phase IIb trials. 3:00PM BMS-927711 Company: Bristol-Myers Squibb Meant to treat: migraine Mode of action: antagonist of the receptor for calcitonin gene-related peptide- increased levels of this peptide have been reported in cases of migraine Medicinal chemistry tidbits: This team recently published an orally bioavailable CGRP inhibitor, BMS-846372 (ACS Med. Chem. Lett., DOI: 10.1021/ml300021s). However, BMS-846372 had limited aqueous solubility, something that might make its development challenging. To improve that solubility, the BMS team sought to add polar groups to their molecule, something that’s been tough to do with CGRP inhibitors historically. In the end, the team managed to add a primary amine to BMS-846372’s cycloheptane ring while maintaining CGRP activity, leading to BMS-927711. Status in the pipeline: Phase II clinical trials 3:05 lots of questions from the audience for this talk! One questioner notes (as was noted in talk) that 4 CGRP inhibitors had gone before this drug in the clinic, and not made it through. Speaker notes that this candidate is more potent than others at CGRP (27 picomolar). 3:53 We’re a bit behind schedule but got plenty of good chemistry… GSK2636771 Company: GlaxoSmithKline Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta....

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Exploring Rational Drug Design
Feb17

Exploring Rational Drug Design

Medicinal chemists strive to optimize molecules that fit snugly into their proposed targets. But in the quest for potency, we often overlook the local physics that govern drugs’ binding to these receptors. What if we could rationally predict which drugs bind well to their targets? A new review, currently out on J. Med. Chem. ASAP, lays out all the computational backing behind this venture. Three computational chemists (David Huggins, Woody Sherman, and Bruce Tidor) break down five binding events from the point-of-view of the drug target: Shape Complementarity, Electrostatics, Protein Flexibility, Explicit Water Displacement, and Allosteric Modulation….whew! Note: Before we dive into this article, let’s clarify a few terms computational drug-hunters use that bench chemists think of differently: ‘decoy’ – a test receptor used to perform virtual screens; ‘ligand’ – the drug docking into the protein; ‘affinity / selectivity’ – a balance of characteristics, or how tightly something binds vs. which proteins it binds to; ‘allosteric’ – binding of a drug molecule to a different site on an enzyme than the normal active site. Regular readers and fans of compu-centric chem blogs such as The Curious Wavefunction and Practical Fragments will feel right at home! We’ll start at the top. Shape complementarity modeling uses small differences in a binding pocket, such as a methylene spacer in a residue (say, from a Val to Ile swap) to dial-in tighter binding between a target and its decoy. The authors point out that selectivity can often be enhanced by considering a drug that’s literally too big to fit into a related enzymatic cavity. They provide several other examples with a ROCK-1 or MAP kinase flavor, and consider software packages designed to dock drugs into the “biologically active” conformation of the protein. Electrostatic considerations use polar surface maps, the “reds” and “blues” of a receptor’s electronic distribution, to show how molecular contacts can help binding to overcome the desolvation penalty (the energy cost involved in moving water out and the drug molecule in). An extension of this basic tactic, charge optimization screening, can be used to test whole panels of drugs against dummy receptors to determine how mutations might influence drug binding. Because target proteins move and shift constantly, protein flexibility, the ability of the protein to adapt to a binding event, is another factor worth considering. The authors point out that many kinases possess a “DFG loop” region that can shift and move to reveal a deeper binding cavity in the kinase, which can help when designing binders (for a collection of several receptors with notoriously shifty binding pockets – sialidase, MMPs, cholinesterase – see p. 534 of Teague’s NRDD review). But these...

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GSK’s R&D Review: Successes & Lessons Learned
Feb08

GSK’s R&D Review: Successes & Lessons Learned

Three years after reorganizing its discovery research activities into small, multi-disciplinary units, GlaxoSmithKline is providing a first peek at how its new approach to R&D is faring. A healthy chunk of its year-end earnings presentation yesterday was devoted to discussing the productivity of its research engine, and what can be expected out of its labs in the next three years. As we described, the goal of its 2008 revamp was to create a biotech-like, entrepreneurial feel within the walls of a big pharma firm: After being one of the first drug companies to create research hubs, or what it calls “centers of excellence in drug discovery,” GSK last year created “discovery performance units” (DPUs) within each hub. Each of the 38 DPUs operating now has a multidisciplinary team of up to 60 scientists focusing on a therapeutic area, a disease pathway, or some aspect of basic biology. GSK also formed a “discovery investment board” that makes funding decisions for the research projects in each DPU. The idea is to bring diverse perspectives on the merits of each project: In addition to [GSK R&D head] Slaoui, the board includes a biotech company CEO, a senior public health official, and GSK’s heads of drug discovery, late-stage development, and business development. DPUs are intended to operate like a biotech company housed in a big pharma firm. Much as a biotech gets funded by venture capitalists, a DPU receives an initial bolus of money and then extra cash when certain project goals are met. Each DPU had an initial review after a year of operation and will undergo another review this month, the 18-month check point. The board meets a last time at the three-year mark. GSK says there are clear signs that the DPU approach is working. Although the company is spending less on R&D and has raised the bar for moving a drug candidate into late-stage development, it has increased the number of molecules in its late-stage pipeline, Patrick Vallance, GSK’s president of R&D told the Haystack. Under the new R&D regime, 22 molecules have moved into late-stage development, and Vallance wants to see 30 molecules pushed forward in the next three years. And in what Vallance believes is a sign that scientists are becoming more ambitious and attempting to do genuinely novel early research, roughly 17 publications in came out of GSK’s labs last year. Prior to the DPU approach, basically no papers were being submitted to prestigious journals, he says. The board, which had its final review in November, decided to shut down three DPUs, and create four new DPUs. Funding for six existing DPUs was upped by more...

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Pharma & Biotech Job Cuts Mount in 2012
Feb03

Pharma & Biotech Job Cuts Mount in 2012

For those keeping track, yesterday’s layoffs at AstraZeneca add to an already substantial list of cuts in the pharma and biotech industries since the beginning of the year. By our tally, nearly 13,000 job cuts, many in R&D, have been announced so far–and we’re barely into February. Here’s where we’re at (and do let us know if we’ve missed any): –AstraZeneca is chopping 7,300 jobs, including 2,200 R&D positions, by 2014. Neuroscience research is being revamped and focused on external partnerships; the company’s Montreal R&D site will be shuttered, and research activities ended at its Södertälje site in Sweden. –Genzyme gave the pink slip to an unspecified number of R&D scientists this week. The layoffs come as Sanofi integrates its big biotech acquisition. –Alnylam is trimming 61 jobs, or 33% of its workforce, in order to save roughly $20 million this year. –BioSante Pharmaceuticals is shedding 25% of its staff, or 21 employees and contractors, after disappointing Phase III results for its female sexual dysfunction treatment LibiGel. –Takeda is axing 2,800 jobs, or 9% of its workforce, following its acquisition of Swiss drugmaker Nycomed. The bulk of the layoffs, which cut across R&D, commercial, operations, and administrative positions, will occur in Europe. –Novartis unveiled plans to shed some 1,960 positions in the U.S. as it braces for generic competition for Diovan, a blood pressure medicine that brought in more than $6 billion in 2010, and an expected drop in demand for its renin inhibitor Rasilez following questions about the drug’s safety. –Human Genome Sciences said it would cut 150 jobs, or about 14% of its workforce, in a move that affects manufacturing, R&D, and administrative activities. –Xoma is shedding 84 workers, or 34% of its staff, as it shifts to outsourcing late-stage and commercial manufacturing, as well as some research. –SkyePharma is cutting 20% of the 101 employees at its site in Muttenz, Switzerland. –Sanofi plans to layoff 100 workers at its Monteal site as part of an overhaul of its Canadian operations. –J&J will trim 126 workers as it closes its Monreal R&D...

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