G-protein-coupled receptors are hot drug targets, and plenty of companies want to know what they look like to get an edge on making new drugs. Despite recent advances, getting X-ray crystal structures for GPCRs is still far from easy.
So companies are joining forces with leading academic labs that solve GPCR structures—those of Brian K. Kobilka at Stanford, Raymond C. Stevens at Scripps Research Institute, Christopher G. Tate at the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, England, and with the start-up companies they’ve each cofounded. This trio of firms is licensing their structure-determining technology and partnering with large drugmakers to crack thorny GPCR targets. And two of the start-ups are showing the world the approach can work through drug discovery efforts of their own.
Kobilka cofounded ConfometRx in 2005 with physician-scientist and spouse Tong Sun. The company is developing a suite of techniques to help companies crystallize GPCRs. “We want to translate some of the technology we’re developing in the lab and make it useful to pharma,” Kobilka says.
One such method is T4 lysozyme fusion technology, which Kobilka’s Stanford team used to determine the structure of the 2-adrenergic receptor, only the second GPCR to succumb to crystallography. Researchers can use the T4 lysozyme protein to replace a loop on the inner portion of a GPCR, providing some stabilization of the flexible GPCR, as well as extra contacts for crystals to form, Kobilka explains. ConfometRx has an exclusive license for T4 technology, but “we generally throw everything we can at a problem,” including T4, antibody strategies, and a host of protein preparation techniques, Kobilka says. His academic lab is also exploring nuclear magnetic resonance technology, something he hopes can someday be part of ConfometRx’s offerings.
“We’d like to be a resource,” Kobilka says. And companies like Bristol-Myers Squibb and Lundbeck have taken them up on that offer by establishing collaborations. “At some point we may want to evolve along the lines of drug development or in silico screening, but right now we’re very small, and we’re focused on developing and refining our technology,” he says.
“It’s hard to pick any one thing we do” to ease GPCR crystallization, says Michael A. Hanson, associate director of structural biology at Receptos. One technique they’ve used successfully involves stabilizing a GPCR with a small compound instead of with a protein. This strategy was successful for solving the A2A adenosine receptor structure in company cofounder Stevens’ lab. Receptos also used that tactic to solve the structure of the GPCR sphingosine-1-phosphate receptor subtype 1, a multiple sclerosis drug target, Hanson says.
That structure helped the company prioritize which chemical scaffolds to pursue in its multiple sclerosis drug discovery program. In January the company announced that one of the small molecules from that program, RPC1063, has reached Phase I human clinical trials.
The molecule was initially derived from a hit discovered in a screen run at the National Institute of Health’s Molecular Libraries Probe Production Center at Scripps. RPC1063’s structure has not yet been disclosed.
In addition to the company’s own drug discovery efforts, Receptos has licensed its GPCR crystal structure determination technology to Ortho-McNeil-Janssen Pharmaceuticals and has announced a partnership with Eli Lilly & Co. to develop small-molecule drug candidates for a GPCR. Hanson declines to disclose the GPCR target or the disease involved in the Lilly deal.
Across the globe from its fellow start-ups, Heptares Therapeutics gets its GPCR X-ray structures with help from thermal stabilization—a targeted mutation technique developed in cofounders Tate and Richard Henderson’s labs at the MRC Laboratory of Molecular Biology. It’s not fully clear how thermal stabilization works, but it keeps the GPCR from falling apart and traps it in a single state, Tate says.
Those stabilized receptors, or StaRs, have helped Heptares reach a major milestone in its GPCR drug discovery partnership with Novartis. “We’ve achieved success with what was a difficult receptor in a new family,” says Fiona H. Marshall, Heptares’ chief scientific officer. Heptares has not disclosed the GPCR target.
Heptares has also uncovered a compound that blocks the A2A receptor, a GPCR that responds to adenosine. The molecule is in preclinical studies for Parkinson’s disease. The company started its drug discovery program before the A2A receptor’s X-ray structure was determined by using a computer model based on the solved structure of a different GPCR to screen a library of molecules called fragments, with lower molecular weights than normal screening collections. Heptares chemists then built out from the fragment to make compact drug candidates, akin to a method called fragment-based drug discovery (C&EN, July 21, 2008, page 15).
The small molecule that emerged from Heptares’ battery of studies has a molecular weight of under 300, which makes it smaller, and therefore better aligned with guidelines for druglike molecules, than other A2A-targeted Parkinson’s drug candidates, Marshall says.
Partnerships with small companies help push GPCR drug discovery forward, says Bristol-Myers Squibb principal scientist Andrew Tebben. “There are very specialized techniques one has to master to be able to crystallize GPCRs,” he says. Several small companies “have that expertise—they know how to handle these proteins,” he says. By combining that know-how with large-company expertise “we hope to achieve more of our goals.”