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...

Read More
Structures May Not Solve Everything
Mar14

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...

Read More