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Additive Approach

Case Study #1: UCB taps deCode for structure-based drug discovery

by Rick Mullin
March 16, 2009 | A version of this story appeared in Volume 87, Issue 11

Credit: DeCode
DeCode Genetics pairs structural biology and chemistry in its discovery techniques.
Credit: DeCode
DeCode Genetics pairs structural biology and chemistry in its discovery techniques.

UCB AND DECODE GENETICS' chemistry and biostructures division aren't saying much about the drugs they are working on in a collaboration announced last month—only that deCode will work with the Belgian company on structure-based discovery of small-molecule modulators of "undisclosed cytokine targets" in the area of inflammation. But the companies are discussing how the partnership advances their strategies to, in deCode's case, further a fragment-based lead discovery technique and, in UCB's, to boost its pipeline.


Additive Approach

The collaboration comes as UCB is working to better coordinate its in-house chemistry and biology capabilities, says Graham Warrellow, vice president of chemistry at UCB's U.K.-based operation. "The time is right to catalyze on what we know about the biologicals world in terms of the types of targets researchers go for and to try to find a way to target these pathways using small molecules," he says.

Not that making chemistry and biology work together efficiently is an easy trick—many have tried and failed. "But I believe the reason people have failed in the past is because they have not used the right assays or approach," Warrellow says. It is also difficult for any one company, he says, even one with sizable biology and chemistry research organizations, to pull this off on its own. That's where UCB's year-old NewMedicines drug discovery group comes in.

Since launching NewMedicines, UCB has forged deals with biotech firms, including deCode, Proteros Biostructures, and SAI Advantium, and has started an alliance with King's College London. "We've tried to create something like an open innovation platform," Warrellow says, "where we access people in industry and academia in stitching together a network."

UCB found an ideal partner for its cytokine inflammation project in deCode's U.S.-based chemistry and biostructures division, Warrellow says. Specializing in protein-protein interactions, the division recently made an initial new drug (IND) filing with the Food & Drug Administration for modulators of the protein phosphodiesterase 4D (PDE4D), which it discovered through a structural biology investigation using molecular fragments to modulate protein-protein interactions.

DeCode has already put three compounds into the clinic and now is looking for a partner to develop the PDE4D modulator as a treatment for cognitive deficiency associated with Alzheimer's disease and other disorders, according to Lance Stewart, president of the biostructures division, located in Bainbridge Island, Wash. The firm is also promoting its discovery technique, called Fragments of Life, to third parties such as UCB. Fragment-based drug discovery has been gaining attention recently (C&EN, July 21, 2008, page 15).

DeCode's approach focuses on a unique application of chemistry to biology, claims Alex Kiselyov, president of the company's chemistry division in Woodridge, Ill. "Instead of using high-throughput screening or cell-based screening, we use high-throughput crystallography and chemistry in tandem," he says. Nuclear magnetic resonance and surface plasmon resonance are also applied to gain insights into how molecule fragments bind to targets, he adds.

"Science is science and drug discovery is risky, and anything can happen.But we plan for risk and not failure."

"THE IDEA is to understand where the molecule binds and what it does, exactly, to the active site, to the allosteric site, or to an interface of the protein-protein interaction," Kiselyov says. "Chemists digest this information, evolve the particular molecule into a lead candidate, and feed it back to structural biology. Structural biology reiterates its round of crystallography and feeds this information to chemists, and on and on we go."

UCB's Warrellow sees a distinct advantage to fragment-based discovery over the more widely used high-throughput approaches that vet complex, high-molecular-weight compounds. "In the days of the combinatorial library, you would generally be picking up high-affinity interaction, but efficiency was often quite low," he says. "It is quite interesting that the output from the industry during that period went into a kind of decline."

The additive process of building up fragments is more logical than the reductive one of determining what part of a larger molecule binds to a target, Warrellow argues. "Having a crystal structure of a fragment binding with the protein demonstrates to the chemist how that small piece of the molecule interacts with the target," he says. "It clues the medicinal chemists in on how to alter the structure and where to add functional groups to molecules in order to increase the binding."

DeCode's Fragments of Life library complements the compounds and fragments in UCB's own collection, Warrellow says. Just as important, deCode researchers will serve as an extension of UCB's in-house R&D team. "Now we are treating collaborators as collaborators, not service providers," he adds. "This is a change for us."

UCB is also gaining access to expertise in protein-protein interactions. "The reason we went to deCode is that we just believe they are one of the best structural biology groups in the world," Warrellow says. "They have a very strong capability to clone, express, and purify proteins and then take them further into structural studies."

UCB also considered deCode's pharmaceutical chemical production capabilities, which can produce Phase III quantities, a plus, Warrellow says, but there is no guarantee that the partnership will go that far. In fact, the deal is open-ended as to how far it will proceed; it will continue as long as it adds value to what UCB can do on its own to find small molecules that modulate protein interactions, he says.

DeCode's Stewart agrees the end-point of the collaboration will be determined by performance. "We have managed to put together a collaborative program where the goal is an IND. And there is a commitment to achieving that goal from both sides," he says. "Science is science and drug discovery is risky, and anything can happen. But we plan for risk and not failure."

Both companies agree that the collaborative nature of the relationship is likely to prolong it, and both see a long-term partnership as ideal. Warrellow also sees it in the context of a trend toward collaborative work between commercial drug research enterprises.

"It is the only way forward for the drug industry," Warrellow says, noting that UCB has a similar working arrangement with the other contract research organizations and has other deals it has not announced. "The issues that we deal with in discovering new drugs are so complex that even in the very large organizations, it is difficult to provide the right balance of all the skill sets. I am excited about the future; having a more open innovation approach is a much more invigorating way to work," he says.


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