COMPANY TO WATCH | Serenex's chemoproteomic affinity platform streamlines drug screening 

By Kevin Davies 

April 16, 2004 | Behind the unlikely facade of a historically listed garage on the North Carolina state registry, scientists at Serenex are developing a chemoproteomic platform that could transform the drug discovery business.

Founded in 2001 by Tim Haystead of Duke University Medical Center, Serenex began life as a platform company intending to evolve into an instrument company. Now it is dedicated to drug discovery, under the direction of Richard Kent, former chief medical officer at GlaxoSmithKline (GSK).

Serenex uses a proprietary matrix, or affinity media, to bind purine-binding proteins — a group of thousands of proteins including kinases, chaperone proteins, and other clinically important proteins that use purine molecules (e.g., adenosine triphosphate, or ATP) as co-factors. "The purine-binding proteome represents up to 40 percent of the druggable genome," says Anil Goyal, vice president of business development, and formerly with Millennium Pharmaceuticals.

"The matrix is the core of our approach," Goyal continues. "It allows us to bind purine-binding proteins reversibly from any tissue source. Then we take a compound and challenge this matrix. What comes out are proteins being displaced from the matrix, so all the proteins that are eluted are those with binding affinity for the drug."

Serenex Essentials Focus: Chemoproteomic drug discovery Scientific founder: Tim Haystead Current funding: $17 million Current staff: 37 Location: Durham, N.C.

Rather than screen thousands of compounds against a single target, Serenex screens individual small-molecule drug candidates against a plethora of proteins. "It's not about throughput in the number of compounds, but the number of targets in the same assay," Goyal says. The approach is not only highly selective but also extremely efficient — only milligram quantities of each compound are required, orders of magnitude less than traditional methods.

As the drug-binding proteins elute out of the media, they are separated through a 1-D acrylamide gel. The gel is scanned, and the protein bands excised by a custom-built instrument. The proteins are identified by mass spectrometry (high-throughput Applied Biosystems MALDI-TOF-TOF and Q-TOF for confirmation). Goyal jokes: "The functioning garage door comes in handy when we need to move mass specs in and out."

IT'S A FAMILY AFFAIR: The purine-binding proteome offers a large number of attractive drug targets, but some drugs exhibit promiscuous binding (red dots).

Since its first deal with Pfizer, Serenex has signed partnerships with several marquee customers, including Chiron, GSK, Lilly, Roche, and Aventis. Most begin with pilot agreements. "We're profiling their compounds, the selectivity of their molecules, or we're identifying possible targets for toxicity," Goyal says. "By knowing the secondary targets, we can explain sources of secondary pharmacology."

For example, Serenex worked for the National Cancer Institute on the oncology drug geldanamycin, which had been halted in Phase I trials for toxicity reasons. The prime drug target is a heat shock protein (HSP90), but Serenex identified a secondary target called ADE2, an enzyme involved in purine biosynthesis that could explain the toxicity. Serenex found three compounds that bound selectively to HSP90 that were not only active but also less toxic in humans. One is in Phase II trials being conducted by Kosan Biosciences.

Noting the perceptible trend in pharma circles toward broadly targeting drugs for certain diseases, including cancer, Serenex can identify compounds that Goyal says act in a "very selective or broadly effective manner. The current thrust of hitting multiple targets in multiple pathways would give you a lot more efficacy. Gleevec is an example of that."

Serenex is also ramping up its internal drug discovery effort, having expanded its chemistry group under R&D head Steve Hall, formerly of Lilly and Bristol-Myers Squibb. "We're able to devote between 60 and 90 percent of our resources to internal drug discovery," Kent says, "and fully meet our collaborative obligations."

Early efforts focus on oncology and inflammation, but Kent is particularly enthused about antivirals. "We have found a target and a good set of molecules against that target," he says. Serenex currently has 37 employees, and continues to grow. An expansion of a B financing round will close this summer.

The development of lead molecules will help raise more money — some will be licensed to partners, and others will be developed internally. "We'll be outsourcing quite a bit of the preclinical work and maybe some chemistry as well," Goyal says. There is of course competition from companies such as GPC Biotech, Ambit Biosciences, and ActivX. And then there are "the folks who believe they can do this internally," Goyal says, while not sounding entirely convinced.

Serenex's name is derived from "serendipity." After all, "drug discovery is driven by serendipity in a lot of ways," Goyal says. Then again, some companies make their own luck.