Heptares solves first X-ray structure of Family B GPCR, but full details not yet public
Sep17

Heptares solves first X-ray structure of Family B GPCR, but full details not yet public

In what might be the year’s biggest molecular teaser, Heptares Therapeutics has announced that it has solved the first X-ray crystal structure of a G-protein coupled receptor in the Family B subclass. The work provides the first structural insights into a protein family that includes sought-after drug targets such as GLP-1 for diabetes and CGRP for migraine. Largely because of that drug discovery relevance, however, Heptares is choosing to keep its structure somewhat close to the vest. Officials presented views of the structure, of a GPCR called Corticotropin Releasing Factor (CRF-1) receptor, at conferences on Friday and Monday. But Heptares CEO Malcolm Weir says his team has no immediate plans to publish the structure or to deposit coordinates into the repository known as the Protein Data Bank. The structure, Weir says, is another success for Heptares’ GPCR stabilizing technology, StaR. The technique involves targeted mutations that help to trap a GPCR in a single biologically-relevant state. In the case of CRF-1, Weir says, the stabilized receptor is captured in the “off” state. The structure itself, which is at a resolution of 3 Ångstroms, has the 7-helix membrane-spanning structure typical of GPCRs. However, CRF-1’s architecture is rather different from receptors in Family A, the only GPCR family for which X-ray structures had been available until now, Weir says. “The overall shape of the receptor looks different, the orientation of the helices looks different, and there are detailed differences within helices that are at analogous positions in Family A receptors,” he says. He notes that there are differences in helices 6 and 7, which undergo important motions during GPCR activation. “This is an important breakthrough, although fine details of the structure and release of coordinates may still be some time away,” says Monash University’s Patrick Sexton, an expert in Family B GPCRs who was at Friday’s talk. The structure, he says, confirmed researchers’ expectations that the major differences in membrane-spanning helices between Family A and Family B receptors would occur on the extracellular side. “There was a very open and relatively deep extracellular binding pocket, with the receptor having a ‘V’ shaped appearance,” he says. This open pocket likely contributes to medicinal chemists’ difficulties obtaining high affinity small molecule ligands for Family B receptors, he suggests. That open pocket might be involved in another Family B GPCR mystery, according to Roger Sunahara, also in attendance Friday, who studies GPCRs’ molecular mechanisms at the University of Michigan, Ann Arbor. All Family B GPCRs, including CRF-1, have a large domain at their amino-terminus that contains large portions of their ligand binding sites. That domain was not included in this structure, he says, but...

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What Pfizer’s Bapineuzumab Failure Means for Parkinson’s Disease Research

The spectacular—and largely anticipated—failure of the Alzheimer’s treatment bapineuzumab has caused an outpouring of stories questioning what went wrong and what it means about pharma’s approach to R&D. Pfizer, Johnson & Johnson, and Elan, the developers of bapineuzumab, are taking a beating in the press for investing so heavily, not to mention raising the hope of so many patients, in a therapy that had not shown strong signs of efficacy in early trials. Most stories are focused on the implications for Alzheimer’s research and, more generally, the pharma business model given the hundreds of millions of dollars the three companies sank into bapineuzumab. But news of its failure also resonated in research communities focused on other neurogenerative diseases, like Parkinson’s disease and Huntington’s disease, marked by protein aggregation. I checked in with Todd Sherer, CEO of the Michael J. Fox Foundation to understand what Parkinson’s researchers might learn from the disappointing data from bapineuzumab. Sherer believes there are scientific and business ramifications of the results, both of which might have a chilling effect on neuroscience research. From a scientific perspective, some are declaring the failure of bapineuzumab the nail in the coffin of the amyloid hypothesis, the theory that the beta-amyloid, the protein responsible for the plaque coating the brains of people with Alzheimer’s disease, is the primary cause of neuron death in the disease. Bapineuzumab, which blocks beta-amyloid, was one of a handful of treatments to test the hypothesis in the clinic. So far, every drug to reach late-stage trials has failed. Sherer isn’t convinced bapineuzumab is the nail in the amyloid hypothesis coffin. “Obviously the results are very disappointing given the level of interest and investment that’s been put forward for this therapy,” Sherer says. “I don’ think that the result is a definitive answer to the amyloid hypothesis because there are many different ways to target amyloid aggregation therapeutically.” Parkinson’s researchers are also trying to learn from the setbacks in Alzheimer’s and apply that to studies of drugs targeting alpha synuclein, the protein that clumps together in the brains of people with Parkinson’s disease. “One of the things that is a learning for us in Parkinson’s is really to try to be as smart and informative as we can be in the early clinical trials,” he says. In Alzheimer’s, for example, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a collaboration between government, academic, and industry scientists, was formed in 2003 to identify biomarkers that can be used both in the diagnosis of the diseases and in the clinical development of Alzheimer’s drugs. However, Sherer points out that while progress in the ADNI initiative has been promising, it...

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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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Wither Neuroscience R&D? Pfizer’s Ehlers Doesn’t Think So

In this week’s issue, I look at the perceived exodus by pharma companies from neuroscience R&D. Between AstraZeneca’s recent cutbacks, the closure of Novartis’ neuroscience research facility in Basel, and earlier moves by GSK and Merck, industry watchers are understandably worried that the neuroscience pipeline will dry up. One person who isn’t worried is Michael Ehlers, Pfizer’s chief scientific officer for neuroscience research. Ehlers came to Pfizer a year and a half ago from Duke, with the explicit mission to revamp how the company finds and develops drugs for brain diseases. The scientist is convinced that the field is ripe for new and better drugs, and that by staying in the game, Pfizer will be in a good position to capitalize on what he believes will be a healthy flow of new discoveries. Many drug companies argue that the risk in neuroscience simply doesn’t justify the investment. The overarching sentiment is that the brain is still a black box: good targets are few and far between; clinical trials are long and unpredictable; regulatory approval is tough; and generic competition is plentiful. For many big pharma firms, the math just doesn’t add up. “I personally don’t find that calculus to give you the total picture,” Ehlers says. Shifting resources away from neuroscience to focus on areas like oncology, where the environment looks favorable—clear clinical trial endpoints, the opportunity for fast-track approval, an easier chance for reimbursement from payors—only makes sense in the short term, Ehlers says. But that thinking “is short sighted as to where the fundamental state of biology is in neuroscience,” he says. Why is Ehlers so encouraged about a field that so many are walking away from? He believes that neuroscience is poised to benefit from the kind of genetic links that generated so many targets—and eventually so many targeted-drugs—in oncology. “There is going to be kind of a revolution in the next five years—it’s not going to be tomorrow…but you have to think about that inflection of opportunity over the five-to-ten year time horizon.” To take advantage of each new genetic clue, Ehlers has revamped Pfizer’s approach to neuroscience R&D. As this week’s story explains: In the past, big pharma often gave its scientists a mandate to work in areas such as Alzheimer’s or schizophrenia, regardless of tractable drug targets. Now at Pfizer, Ehlers says, his team is “indication agnostic.” Any program that Pfizer undertakes must have a critical mass of biological knowledge—for example, human genetics, human phenotyping, and evidence of dysfunctional neurocircuits—to convince Ehlers it’s worth pursuing. “We start there,” he says. “That hasn’t always been the case.” Moreover, Pfizer no longer relies on mouse...

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Biogen Idec Reveals Clinical Data for (Really) Small Oral MS Drug BG-12
Nov02

Biogen Idec Reveals Clinical Data for (Really) Small Oral MS Drug BG-12

Biogen Idec made a splash last week when its oral medication for multiple sclerosis (MS), BG-12, was found to reduce relapses in 44-53% of nearly 3,800 patients in two separate Phase 3 clinical trials (CONFIRM and DEFINE, respectively). Continued hopes for an orally available, non-injectable MS treatment have created a race between Biogen Idec and several other firms, as C&EN’s Lisa Jarvis examines in a 2009 MS cover story. In fact, so much has changed in 2 years that two of the six Phase 3 drugs mentioned in that article – Teva’s laquinimod and Merck’s cladribine – have already been withdrawn from competition. So what’s the secret sauce behind BG-12? Many pharmaceuticals are small molecules with multiple heteroatoms and aromatic rings, but not BG-12: it’s just dimethyl fumarate! A search for ‘fumarate’ on pubs.acs.org returned >4800 hits, which gives you an idea of its common use in several organic reactions: [3+2] cycloadditions, Diels-Alder reactions, and Michael additions. Interestingly, dimethyl fumarate is the all-E stereoisomer; the Z-configuration, where the two esters are on the same side of the central double bond, goes by the tagline ‘dimethyl maleate’ and does not seem to possess anti-MS effects. Very small molecules such as BG-12 (molecular weight = 144) are notoriously tough to use as drugs: they hit lots of enzymatic targets, not just the intended ones, and tend to have unpredictable side effects (see Derek Lowe’s 2005 article regarding the FDA “approvability” of several common drugs today). Toss in BG-12’s alkylating behavior to boot (fumarates can interact with nucleophilic amines or sulfides at multiple sites, including enzyme active sites), and you have to wonder how it functions in the body. Well, so do scientists. A 2011 review implicates up to 3 potential biochemical mechanisms – the Nrf2 pathway Lisa mentioned in the 2009 piece, T-helper phenotype 2 interleukin upregulation (IL-4, IL-10, IL-5, which “change gears” for immune system functioning), and CD62E inhibition, which controls adhesion of blood cells to inflammation sites. Side notes: Flavoring chemists have added fumaric acid, the parent diacid of BG-12, to industrially-prepared foodstuffs such as baking powder and fruit juices since the 1930s. A darker side of dimethyl fumarate emerges when you consider its non-medicinal use: certain furniture companies applied it to new upholstered chairs and sofas to stop mold growth. This unfortunately caused several cases of severe skin irritation, which a 2008 exposé in London’s Daily Mail likened to actual burns....

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