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By Deborah Janssen

August 18, 2004 | The recent launch of the NIH Chemical Genomics Center (NCGC)—the first component of the NIH Roadmap—marks a major step in the creation of a nationwide network that aims to provide researchers with innovative chemical tools for use in biomedical research.

“We’re making small-molecule tools available to those in the public sector who haven’t had access to them before,” says Christopher Austin, NCGC director and NHGRI’s senior advisor to the director for translational research. As many as 10 extramural chemical genomic pilot centers—to be announced next spring (see grants1.nih.gov/grants/guide/rfa-files/RFA-RM-04-017.html)—will be funded at academic institutions across the country to build and coordinate the new Molecular Libraries Screening Centers Network (MLSCN).

While small-molecule compounds have been the mainstay of drug development efforts by pharmaceutical and biotech companies for years, only a handful of researchers in academia, government, and nonprofit institutions have enjoyed the opportunity to tap into such libraries. Importantly, the same characteristics that make small molecules useful for medicinal purposes also make them valuable for studying basic cell biology (see Conquering Infinity with Chemical Genetics, Feb. 2003 Bio-IT World, page 48).

The small-molecule library that will be screened at the NCGC and the other MLSCN centers will consist initially of some 100,000 chemically diverse small molecules with both known and unknown activities. This collection will be expanded through synthetic and isolation initiatives to increase its chemical diversity, in order to target the total set of biomolecular surface domains that are capable of interacting with a small molecule.

Because the objective of the NCGC and the MLSCN is to develop research tools, not necessarily drugs, the types of molecules contained in the library will be much broader than those typically screened in biopharma, including non-“druglike,” toxic, and natural compounds. “The genome is a big place, and a chemical collection of maximal diversity is needed to empower the research community to explore the biology encoded by it,” Austin says.

The NCGC anticipates screening more than 100,000 small-molecule compounds in multiple high-throughput assays during its first year of operation. Assays will be developed by investigators and selected by peer review based on biological importance and technical feasibility. Following further assay optimization and high-throughput screening, hits from the screens will undergo rigorous validation and chemical analog optimization to produce a useful in vitro chemical probe of the relevant biological event.

To facilitate the center’s goals, the NCGC will use Kalypsys’ suite of ultra-high-throughput target and pathway screening technologies, capable of screening more than 1 million compounds per day in a variety of biochemical and cellular assays. The spectrum of assays that will be screened will be broader than that screened in industry.

“The private sector understandably tends to focus on the ‘druggable genome’—that set of molecular targets thought to be amenable to functional perturbation by a small molecule for medicinal or therapeutic purposes,” Austin explains. “In contrast, the NCGC, and the MLSCN as a whole, has exploration of the entire genome as its mandate—virtually any biological target or cellular phenotype is of interest to us.”

The MLSCN will have the ability to screen for activators, inhibitors, and binders of proteins, as well as compounds active in cellular reporter assays, phenotypic cellular assays, and whole organism assays, if those organisms are small enough to fit into multiwell plates.

In keeping with the tradition of the Human Genome Project, all of the data and resulting materials will be deposited in a central database called PubChem, which will be managed by the National Center for Biotechnology Information and made publicly available. “The goal is to make the compounds and the data associated with them available to as many people as rapidly as possible,” Austin says.

"This NIH effort will act as a supersized core facility for small-molecule screening for the broader scientific community," says Brent Stockwell, assistant professor of biological sciences and chemistry at Columbia University. "The equipment and infrastructure needed for sophisticated small-molecule screening is effectively too big and expensive for most universities to implement. Therefore, NIH has developed the elegant concept of a national ‘supercore facility’ that will provide this technology to the biomedical community. Think of it as the biomedical equivalent of [a] cyclotron."

PubChem will go live this fall, and the entire network is expected to be fully operational by mid-2005.

Sidebar: The Promise of Chemical Genomics
“A promising example of the gene-based approach to therapeutics is ‘chemical genomics.’ Providing such access more broadly … could lead to the discovery of a host of probes for biological pathways … Also needed are more powerful technologies for generating deep molecular libraries … A centralized database of screening results should lead to further important biological insights … Generating molecular probes for exploring the basic biology of health and disease in academic laboratories would not supplant the major role of biopharmaceutical companies in drug development, but could contribute to the start of the pipeline.” —

Francis Collins et al., Nature 2003.

 





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