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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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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Takeda’s Diabetes Drug Candidate TAK-875 In Phase III Trials
Oct19

Takeda’s Diabetes Drug Candidate TAK-875 In Phase III Trials

Takeda Pharmaceutical today announced it has begun Phase III clinical trials of TAK-875, a first-in-class drug candidate for treating type 2 diabetes. The experimental therapy activates GPR40, a G-protein-coupled receptor that resides in pacreatic islet cells. The TAK-875 story is as much about the biology of the target as it is about the molecule itself. And it’s a story that owes much to the company’s willingness to delve into uncharted territory. In the early 2000s, scientists knew GPR40 existed, but didn’t know what GPR40’s purpose was in the body. Plenty of proteins fit this description– they’re called “orphan receptors” in the industry parlance. Much of Takeda’s drug discovery strategy is based on figuring out what orphan receptors do. In a 2003 paper in Nature (DOI: 10.1038/nature01478), Takeda laid out what it learned about GPR40. The receptor responds to a variety of long-chain fatty acids. In response to fatty acid binding, GPR40 activates and boosts insulin secretion from pancreatic beta cells. GPR40 became a viable drug target for Takeda for several reasons. First, one of the hallmarks of type 2 diabetes is a reduction in insulin secretion from pancreatic beta cells, something GPR40 activation could help counter. Second, G-protein-coupled receptors are established drug targets– and GPR40 happens to be in the class of GPCRs for which researchers know the most about structure— the Class A, or rhodopsin-like, GPCRs. (Note: other GPR-type receptors are diabetes targets as well– C&EN contributing editor Aaron Rowe has written about Arena Pharmaceuticals’ activators of GPR119 as diabetes drug candidates.) Takeda used structural knowledge to its advantage in the discovery of TAK-875 (ACS Med. Chem. Lett., DOI: 10.1021/ml1000855). Researchers were able to build a model of GPR40 based on its similarity to GPCRs of known structure, and dock potential drug candidates inside to see how well they could bind. This is far from the only drug discovery story that has to do with “de-orphanizing” orphan receptors. In fact, as far back as 1997, pharmaceutical company researchers were writing about orphan receptors as a neglected drug discovery opportunity (Trends Pharmacol. Sci., DOI: 10.1016/S0165-6147(97)90676-3). And of course, just because researchers have “de-orphanized” a receptor doesn’t mean all of the complex biology is pinned down. Case in point: the PPAR receptors (J. Med. Chem., DOI: 10.1021/jm990554g). Despite these receptors’ promise as targets for obesity and diabetes, drugs designed to target them have tanked in development or had unexpected problems after arrival on the market (read: Avandia). So as TAK-875 enters Phase III trials, the news might be about the drug candidate’s clinical performance, but you can be sure that Takeda’s researchers are still working hard to unravel as much...

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Structures May Not Solve Everything

This week’s C&EN cover story is about how X-ray crystal structures of G-protein coupled receptors (GPCRs) help the hunt for new drugs. GPCRs are already a major target for drugs (if not the most popular drug target), but until recently, researchers knew little about the finer points of their structures. As I mentioned in that story, those high-resolution protein pictures aren’t a panacea, and they won’t replace established drug-discovery technology so much as complement it. I didn’t have room to flesh out that idea in print, so I’m posting a few researchers’ thoughts on this area here today. Some scientists thought that GPCR X-ray structures are so far of limited utility for discovering allosteric drugs, a class of GPCR-targeted drugs that can dial activity up or down rather than turning it on or off. Some GPCR-targeted drugs on the market already work this way, such as the HIV medication Maraviroc, and many more are in development. (As an aside, I feel as though every time I attend an ACS meeting talk about GPCRs, the room is packed). “It’s the chicken and the egg story,” says Robert Lutjens, head of core biology at Addex Pharmaceuticals, which specializes in GPCR drug discovery. To get an X-ray structure of an allosteric molecule binding to a GPCR, which would be useful for developing virtual screens, one would first need to find just the right allosteric molecule—one that stabilizes the GPCR sufficiently to enable it to be crystallized. That’s difficult to do, so powerful biological assays are still critical for finding molecules that act at allosteric sites, Lutjens says. Allosteric drugs aside, Rockefeller University biochemist Thomas P. Sakmar told me that GPCR structures don’t show the detailed dynamics of GPCRs in complexes with protein partners and in the environment of the cell membrane—information he says will be critical for developing drugs. Researchers should further develop nuclear magnetic resonance methods and computational methods to study the molecular motions of GPCR complexes, he says. One computational technique, molecular dynamics, is designed to simulate atoms’ motions over time like a virtual microscope, but it is in its infancy in the GPCR field, he adds. Finally, GPCR structures don’t take decades to solve any more, but the structural biology is still a bit slower than what pharmaceutical drug development projects typically require, says Brian K. Kobilka, a Stanford biochemist who specializes in solving GPCR structures. It might be possible to get a new GPCR target’s structure in the first year of a drug discovery program, but it’s not something to bank on just yet, he adds. And without a structure or a reliable model, virtual screening isn’t an...

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How Do You Get From Picture to Pill?

Just about every time C&EN covers a newly-solved structure of a G-protein coupled receptor, we throw in a sentence about how the structure has big implications for drug discovery. And rightly so- G-protein coupled receptors (GPCRs) are one of the top types of proteins targeted by drugs. But just what does that statement mean? It’s not like a medicinal chemist can look at that structure and instantly come up with a drug that controls the protein and treats a disease. I’m in Taos, New Mexico, at a Keystone Symposium called “Transmembrane Signaling by GPCRs and Channels”, where I’m talking to researchers who take the information from pretty pictures of membrane-spanning proteins and use it to build viable drug candidates. Take a look at the Keystone Symposium’s program, and you’ll see a handful of speakers from industry. For instance, I’ve already heard a talk from Fiona Hamilton Marshall at Heptares Therapeutics and today (Wednesday) I will hear one from Kenneth E. Carlson at Anchor Therapeutics. I’ve also had the pleasure of meeting two folks who I’ve only spotted before on Twitter- Peter Nollert (@reducentropy) of Emerald Biosystems and UCSF postdoc Ryan G. Coleman (@rgcjk). This conference is already giving me more information than I can handle about solving GPCR structures- start drinking from the firehose with this overview of the tricks of the...

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