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DiscoverX Collaboration Enables NCGC to Add to Stable of Cell-Based Assay Techs

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The National Institutes of Health's Chemical Genomics Center will evaluate DiscoverX's PathHunter brand of homogenous cell-based assays for intracellular protein translocation as a tool to screen specific targets of interest for the Molecular Libraries Roadmap Initiative, DiscoverX said last week.

With the agreement, the NIH continues to add to its growing stable of cell-based assay tools to fulfill its mission as spelled out in the Molecular Libraries Roadmap — to conduct industrial-scale screens of its small molecule repository as a way to extend the findings of the Human Genome Project into a similarly comprehensive map of drug targets, protein interactions, and disease phenotypes.

For DiscoverX, the deal should serve as a proving ground for its relatively new PathHunter line of cell-based screening assays, which may help the company sell more of the assay kits to the pharmaceutical drug-discovery market. At the very least, it may lead into revenue from the NIH itself.

NCGC has also evaluated or is currently evaluating cellular analysis technology such as Odyssey Thera's protein complementation assay cell lines (see CBA News, 8/29/2005 and TTP Labtech's Acumen Explorer scanning cytometer (see CBA News, 2/22/2005).

"The NCGC is forging collaborations with developers of assay, instrumentation, and software technologies to evaluate and identify those which will enable the NCGC in its mission to identify and develop chemical probes for the academic community," Jim Inglese, director of biomolecular screening and profiling at NCGC, wrote to CBA News in an email.


"The NCGC is forging collaborations with developers of assay, instrumentation, and software technologies to evaluate and identify those which will enable the NCGC in its mission to identify and develop chemical probes for the academic community."

"The NCGC is committed to expanding assayable genome space, and this expansion will frequently require new technologies," Inglese's email continued. "To the degree that companies share our commitment and have developed assay platforms to do that, we are interested in testing the new technologies in our own hands, and in making those results — good or bad — available to the research community via PubChem."

"If this works the way that the NIH expects it to work, then it will lead into a purchase," Sailaja Kuchibhatla, DiscoverX's vice president for business and development told CBA News last week. "Right now it's a technical collaboration at this stage."

This is crucial to the company, which derives most of its revenues from the sale of assay kits. "We have a distribution agreement with [GE Healthcare], and we do occasional custom assay development, but the bulk of our revenues are from assay reagents and novel technologies," Richard Eglen, DiscoverX's CSO told CBA News recently at IBC's recent Assays and Cellular Targets meeting in Bellevue, Wash.

"The people running the initiative at the NIH are very familiar with the enzyme fragment complementation technology that this is based on, and some of the benefits it offers," Kuchibhatla said. "At previous positions at Merck and several other places, [NIH researchers] actually have worked with it, so from that perspective it's not really an evaluation.

Kuchibhatla added that the NIH hopes to bring in assay-ready cells from DiscoverX and "quickly test a few compounds … and then there would be a larger set of libraries that would be put against it."

Inglese also wrote in his email that data produced from the DiscoverX collaboration "will be subject to the same data-release policies (i.e., immediate deposition into PubChem) that all of our other assays are. This is a win-win-win: a win for us since we get access to new assay technologies, a win for the companies since they get their technologies tested in a real-world setting and full access to the data, and a win for the research community, who gets unfettered access to all the data generated in the collaborations."

The timing for DiscoverX couldn't be better to possibly gain industry traction, as the company plans to roll out "several more" versions of the product to complement the pair of assays it currently offers, Eglen told CBA News.

"The goal is to release initially a series of homogeneous assays to measure nuclear translocation," Eglen said. "We're also going to be releasing a mitotic cell assay, where again, you can do this homogeneously — the whole concept being built around beta galactosidase complementation and taking this into primary screening.


"To the degree that companies share our commitment and have developed assay platforms to do that, [the NCGC is] interested in testing the new technologies in our own hands, and in making those results — good or bad — available to the research community via PubChem."

PathHunter is based on DiscoverX's patented enzyme fragment complementation technology, in which a small, inactive fragment of the enzyme ß-galactosidase (called ProLabel) is either conjugated to, or, in the case of the NIH collaboration, expressed in live cells. Then, a larger reagent — the other part of the B-gal — is added to the cell mixture, and subsequently forms a fully functioning B-gal that can hydrolyze a reporter molecule for detection.

In the case of PathHunter, the larger ß-gal fragment is restricted to the cell nucleus, and the protein target of interest is expressed in the cytoplasm as a ProLabel fusion protein. A chemiluminescent signal results only after translocation of the ProLabel-tagged target into the nucleus.

This, along with several of DiscoverX's other assays based on EFC, are part of the company's efforts to move cell-based assays beyond high-content screening in secondary assays and target validation, and into high-throughput primary drug screens.

"That's our vision," Eglen said. "The amount of information is somewhat less because it's a whole-well read, but the throughput is orders of magnitude higher. We view our approach as very synergistic to high-content screening. It enables you to do the primary screening, select out the leads, which can then be taken into HCS, where you do the more sophisticated cellular analysis."

Further on, DiscoverX is eyeing live-cell versions of its enzyme fragment complementation-based assays — 'live' implying that the cells will still be intact and alive during the detection portion of the assay. This is in part due to customer demand and in part due to industry trends.

"The goal is to give everybody complete flexibility," Eglen said. "The other advantage, of course, is that you can take the live-cell assay into other methods of analysis, such as flow cytometry."

Although there is no specific timetable for the development of such assays — they are still in the R&D stage, Eglen said — DiscoverX has already begun to explore this space commercially via collaborations, such as the one forged with Canadian start-up PatoBios (see related story, this issue).

— Ben Butkus ([email protected])

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