Center Takes on Challenge of Early Drug Discovery

By Eric Sauter and Mika Ono

The Scripps Research Institute's $80-million grant from the National Institutes of Health (NIH) in 2008 came with a challenge: to spur the discovery of proof-of-concept molecules that could be useful in developing new treatments for a large number of human diseases.

At the Scripps Research Molecular Screening Center, to date remarkable strides have been made toward that goal, thanks to the expertise of researchers in biology and chemistry from both the Scripps Research California and Florida campuses as well as "high-throughput" robotics at Scripps Florida that can test thousands of compounds at once for activity against various biological targets.

Scripps Research was recently the first of four NIH-funded comprehensive Molecular Screening Centers nationally to optimize a compound from the molecular library collection and introduce it into humans for clinical testing. The compound (an S1P1 receptor agonist with novel receptor interactions) was first discovered by the center's principal investigator Professor Hugh Rosen and optimized by Professor Ed Roberts, and has potential for the treatment of multiple sclerosis and other autoimmune diseases. Under the auspices of Receptos, a San Diego-based biopharmaceutical firm, the drug candidate entered Phase 1 clinical trials last January.

The reason the Scripps Research center works so well, believes Rosen, is the quality of the faculty on both campuses.

"This is a strong group of people who are goal-directed and a pleasure to collaborate with," he said. "At Scripps, we've also become much closer as an institution as a result of the work. There is now this tangible link between the two campuses—and we see that in the publications. Virtually all of them have contributors from both coasts."

The center has published 82 papers so far, with many appearing in prestigious journals—for example, five papers in Nature, three papers in Nature Chemical Biology, two in Nature Immunology, one in Nature Biotechnology, one in Nature Structural and Molecular Biology, four in the Proceedings of the National Academy of Sciences, and five in ACS Chemical Biology.

In addition, a number of new technologies have been developed and applied to small molecule discovery in ways that have transformed the field. One development is the hydrogen/deuterium exchange technology from the lab of Patrick Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute on the Florida campus. In La Jolla, Professor Raymond Stevens has pioneered high-throughput structural mapping of small molecule interactions with receptors (which bind to molecules, triggering a biological effect). Work at the center has also helped the La Jolla group of Benjamin Cravatt, chair of the Department of Chemical Physiology, develop activity-based assays for ultra-high-throughput screening. This has allowed the identification of inhibitors of enzymes known from genetics to be important in cancer, where the natural substrates are either unknown or unavailable.

There is intense chemistry and probe optimization going on both coasts, Griffin notes, and this is one of the things that sets the Scripps Research effort apart. "Our national footprint is a strategic advantage," said Griffin, co-principal investigator of the Scripps Research Molecular Screening Center who also directs several extended probe development projects within the center. "It gives us a broader reach to bring in high-value targets and have a bigger impact on science and technology.

"A big chunk of what the probe center is about is the use of insightful medicinal chemistry to optimize compounds," he continued. "That is a major distinction between an institution that only runs screens and one that offers a full integration of biology, assay development, target validation, and screening to discover chemical starting points and then validate these compounds."

William Roush, professor of chemistry, executive director of medicinal chemistry, and associate dean at Scripps Florida, added, "We have an outstanding group of medicinal chemists, including faculty, staff scientists and postdoctoral associates—both in Florida and La Jolla—who have done a phenomenal job in deriving in vivo active lead compounds and selective cell-based probes starting from screening hits. The activities of the medicinal chemistry groups are driven by data for increasingly optimized compounds provided by the biochemists and biologists on each project team, as well as DMPK (drug metabolism and pharmacokinetic) data. The integrated capacities of the screening center are extremely impressive and are unmatched at other academic institutions."

A Unique Niche

The high-throughput screening operation itself is overseen by Peter Hodder, a senior scientific director in the Scripps Florida Translational Research Institute and associate professor in the Department of Molecular Therapeutics as well as co-principal investigator of the Scripps Research Molecular Screening Center. The technology is substantial and so is the workload.

In the past five years, Hodder's Lead Identification laboratory has completed more than 90 collaborations (on 130 different biological targets) with academic and industrial partners, tested more than 40 million compounds, and completed more than 200 different high-throughput assays. The compounds used in the screens represent the largest drug-discovery library in academia, with more than 622,000 unique molecules, about 30,000 of which are unique to Scripps Research.

The NIH requires the group to handle 24 collaborative projects annually, although the actual number of ongoing collaborations may reach as many as 50 per year because of project overlap, Hodder said. In addition, Scripps Florida is bringing in collaborators from the private sector in increasing numbers.

"In terms of our business, 15 to 25 percent of our research support now comes from projects outside of NIH funding," he said. "It's word-of-mouth through referrals based on excellent performance."

One of those companies is Envoy Therapeutics, which is located near the Scripps Florida campus. That location is no fluke.

"We considered various areas of the country to establish the company and Scripps Florida was a major factor in settling here," said Steve Hitchcock, Envoy's senior vice president of drug discovery.

Starting with one project with Scripps Florida, Hitchcock said, the company soon committed to an additional three. Envoy employs proprietary technology to identify novel, selectively expressed targets relating to the treatment of central nervous system disorders such as Parkinson's disease and schizophrenia, and, most recently, addiction.

"The quality of the science has been terrific," said Hitchcock, who has an adjunct position at Scripps Florida, "and Scripps Florida has been a great collaborator. We're extremely pleased at the way it has been working out."

Hodder's laboratory has also stepped up its own technology development with creation of the HIAPI-CM, a novel invention that reads the plates used in high-throughput screening for various anomalies such as insufficient compound volume. The new technology helps identify problems with compound plates before screening, eliminating labor-intensive quality control that might otherwise be needed.

Hodder believes Scripps Research is continuing to lead the way and carving out a unique niche in its interactions with industry.

"These industry collaborations will increase because we're able to bring great science to the table," he said. "Companies are realizing there's a wealth of information on targets and classes of targets—the broad knowledge base surrounding the core data that only a place like Scripps Research can provide."

Send comments to: mikaono[at]scripps.edu

Scripps Research was recently the first of four NIH-funded comprehensive Molecular Screening Centers nationally to optimize a compound from the molecular library collection and introduce it into humans for clinical testing. (Photo by James McEntee.)