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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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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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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Is Oral Insulin on the Horizon?
Jun02

Is Oral Insulin on the Horizon?

The Haystack wanted to point readers to a nice piece on oral delivery strategies for biotherapeutics by our colleague Ann Thayer. An injection or IV drip may be perfectly reasonable for diseases like cancer, where drugs are usually given in a hospital setting, but for chronic diseases like diabetes or multiple sclerosis, which require daily or weekly injections, a pill would be much more palatable. That said, it is awfully tough to get effective oral delivery of a big, unwieldy protein. As Thayer writes, “Acids and enzymes in the gastrointestinal tract will chew up a valuable therapeutic protein as easily as they’ll tear into a bite of steak.” Companies are especially keen to develop alternative delivery solutions for insulin. Not only would it represent a major advance for patients, but the market for a better-acting and easier-to-use insulin would be gigantic—insulin sales account for about $15 billion of the global diabetes market. Attempts at inhaled insulin have been a colossal failure. Thayer goes on to describe some of the methods biotech companies are using to enable oral delivery of insulin. Among the players: --India’s Biocon is developing IN-105, an insulin molecule conjugated to a short-chain polyethylene glycol derivative. The technology was originally developed at N.C.-based Nobex, which Biocon bought in 2006. --Ireland’s Merrion Pharmaceuticals is using technology acquired from Elan Corp. to enhance gastrointestinal permeation. In 2008, the company began working with Novo Nordisk on solid oral forms of insulin analogs; the first such analog was put into Phase I trials by Novo in late 2009. --N.J.-based Emisphere Technologies is working with Novo Nordisk on GLP-1 analogs. In January, Novo started a Phase I trial of the first candidate using Emisphere’s Eligen technology. --Isreal’s Oramed is using capsules with an enteric coating, which controls where in the intestinal tract a pill is absorbed. A Phase IIb trial of ORMD-0801 conducted in South Africa showed the drug to be safe and to have a clinical impact on insulin and gluose levels. Oramed hopes to do a Phase II study in the U.S. late this year. --Dallas-based Access Pharmaceuticals is using insulin-containing nanoparticles coated with vitamin B-12 analogs, which pull the complex into...

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Array, Novartis Team for Mek-inhibitor
Apr19

Array, Novartis Team for Mek-inhibitor

Boulder, Colo.- based Array BioPharma is again cashing in on its discovery platform for small molecules that block the protein kinase Mek. Novartis has agreed to pay $45 million out of the gate for ARRY-162, a MEK-inhibitor in Phase I cancer trials, and other back-up MEK-blocking compounds. As part of the Novartis deal, Array could earn up to $422 million in additional milestones as the compound moves through the pipeline. Array is keeping a hand in the project, agreeing to pay for part of the development costs for the compound in exchange for what it calls “a significantly higher royalty rate” for U.S. sales of ARRY-162. ARRY-162 blocks MEK, one of several protein kinases in a cell signaling pathway associated with cancer cell proliferation and survival. The compound is currently in an early-phase study in advanced cancer patients with solid tumors to determine the right dose and assess its safety. ARRY-162 isn’t the first MEK inhibitor Array has married off. AstraZeneca licensed what is now known as AZD6224 as part of a long-standing collaboration around the protein target. Though AstraZeneca continues to develop AZD6224, most notably testing the drug in combination with Merck’s Akt inhibitor MK-2206, Array was freed from the exclusivity of the partnership last year. But in the six years of the pact, the biotech not only earned research funding, but pocketed some $96 million in milestone payments. From the looks of the Novartis deal structure, it looks like the Swiss drug major will pick up where AstraZeneca left off. Array appears to be on a bit of a roll in scoring deals that wed reasonable upfront payments with research funding, while also keeping a healthy slice of future product sales. The biotech scored a $60 million upfront payment in December, when Amgen signed on to jointly develop ARRY-403, a second-generation glucokinase activator in Phase I. Glucokinase “senses” glucose in the pancreas by catalyzing the phosphorylation of glucose to glucose-6-phosphate, a critical first step in metabolizing sugar. Drugs like ARRY-403 enable the pancreas to better sense glucose, leading to increased insulin production. Amgen also agreed to provide funding over the course of a two-year research collaboration around glucokinase...

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