Editor

The phrase "fragment-based screening" might sound to the layperson like some kind of forensic tool for analyzing spent cartridges at crime scenes, but to pharmaceutical firms it's increasingly sounding like money - and maybe even a magic bullet.

As an approach to drug design, it's fairly simple: Find fragments that bind to the active sites of proteins, then match them with other molecules or each other to come up with high-affinity drug leads. Last week, two deals focused on the method made headlines, and both involved biotechnology firms teaming up with pharmaceutical heavy hitters.

Sunesis Pharmaceuticals Inc. and Merck & Co. Inc. made public their agreement to discover oral drugs for viral infections, in which Sunesis is to provide Merck with a series of small-molecule compounds derived from its proprietary fragment-based drug discovery platform called Tethering. Merck will advance them into lead optimization, preclinical development and clinical studies.

Specific money terms were not disclosed, but Merck is paying annual license fees, along with an up-front payment and development milestones, plus royalties. Daniel Swisher, CEO of Sunesis, told BioWorld Financial Watch the deal was "typically structured," which he said generally means a "multi-million dollar" up-front fee.

The Tethering technology, the company said, can turn up quick data about hits, such as stoichiometry (i.e., measures of chemical reaction) and site locations - information hard to get from the usual methods of high-throughput screening, at least not without laborious additional experiments.

Tethering gained Merck's attention last year, when the company tapped Sunesis in a deal to find oral therapeutics for Alzheimer's disease. The arrangements are similar, except that this time around Sunesis is not devoting as much in-house effort, allowing it to instead devote more resources to its own research in oncology.

"A lot of our internal effort right now is in kinases, and they directly modulate a number of major diseases," Swisher noted. Two cancer kinase programs are in the preclinical stage, and Sunesis' lead program is a Phase I cytotoxic cell-cycle modulator known as SNS-595. Sunesis also has deals with Biogen Idec Inc. and with Johnson & Johnson Pharmaceutical Research & Development.

The second agreement highlighting fragment-based drug design teamed Locus Pharmaceuticals Inc. with Procter & Gamble Pharmaceuticals Inc., which entered a collaboration to find a new treatment for diabetes.

Locus will custom-design novel molecules against an undisclosed target protein (but a "not common" one, said Locus CEO Joseph Reiser) by combining high-affinity fragments from its proprietary 40,000-member set, with an aim of devising a drug to regulate blood glucose.

P&G is providing an up-front fee and research support for Locus, which will deploy a computer that cranks out 2.3 trillion calculations per second to identify and characterize all "hot spot" binding sites. Locus' quest for speed and accuracy is helped by its recent deal with IBM Corp. to use the latter's Deep Computing Capacity on Demand center.

The accuracy comes thanks to Locus' algorithms, which need a strong computer to be handled. "They're all under patent application protection," Reiser told BioWorld Financial Watch, with a core patent issued.

Here again, Locus intends to follow its own path of internal drug development while proving the "evolving impact of our unique approach" with deals such as the one with P&G. Among the efforts pursued with partners is one targeting renin for hypertension.

Renin has been getting plenty of attention. Interestingly, Merck late last year signed a $272 million deal with the Swiss firm Actelion Inc. to develop new classes of renin inhibitors for cardio-renal diseases. Novartis AG has the renin inhibitor Aliskiren (better known as SPP100), expected to be the subject of a new drug application filing next year. The Speedel Group, also of Switzerland, developed the drug in its first stages with help from none other than Locus. Speedel in-licensed Aliskiren from Novartis in 1999 and conducted fast-track development through Phase I and Phase II. Then Novartis licensed it back.

Locus, anyway, marches on with its fragment work.

"None of the companies that are working with us have reached the clinic yet," Reiser said, and Locus is some distance away from that stage also, though an internal program for cancer is nearing trials that would enable an investigational new drug application.

Another point of similarity that the Locus/P&G deal shares with the Sunesis/Merck agreement is that Locus gets a boost for internal and external efforts from an earlier move: Locus' buyout in July of Protein Mechanics Inc., which gave Locus simulation technology for making small-molecule drugs.

Those are hardly the only firms exploring the fragment-based approach by building on structure-based design in the U.S. and abroad. UK-based Astex Technology Ltd. bills itself as "the fragment-based drug discovery company," pulling down deals with the likes of AstraZeneca plc. Astex in March 2003 entered a $40 million pact for compounds against Alzheimer's disease and merged last fall with MetaGen Pharmaceuticals GmbH, of Berlin.

The field is tricky. Identifying fragments to work with proves hard because the bits are so small they cannot bind in a convincing, readily identifiable way (although, once located, they can be tweaked for potency). Detecting that first tendency to bind is what Astex does with X-ray crystallography, in its method called Pyramid.

Another name in the space is UK-based Celltech Group plc, which recently agreed to a $2.7 billion takeover by Belgium's UCB SA. Yet another is Graffinity AG, of Munich, which last spring landed a deal with Europe's top biotechnology firm, Serono SA, to work with five target proteins in various disease indications. Combinature Biopharm AG, of Berlin, is yet another firm experimenting with fragments.

Swisher, of Sunesis, said the method is still building steam, providing a leg up on slower, traditional ways.

"It's an area of very active research," he said.

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