Scripps Research Receives Record Federal Grant of More than $80 Million to Screen Molecules for Possible New Drug Development

By Eric Sauter

The Scripps Research Institute has been awarded more than $80 million by the National Institutes of Health to greatly expand the work of The Scripps Research Molecular Screening Center, further strengthening the collaborative efforts of  teams of scientists at the La Jolla, California, and Jupiter, Florida, campuses. The six-year federal grant is the largest ever awarded to Scripps Research.

The Scripps Research Institute Molecular Screening Center will use Scripps Florida's high throughput robotics to screen discoveries made in laboratories in La Jolla and Jupiter, as well as other research institutions, against various biological targets. The goal is to uncover "proof-of-concept molecules" that could be useful in developing new treatments for a large number of human diseases.

The Scripps Research center is one of only four such large centers nationwide. Together with five smaller specialized centers, they comprise the Molecular Libraries Production Centers Network, a part of the National Institutes of Health (NIH) strategic funding plan, the Roadmap Initiative.

"This is a tremendous accomplishment and validation of the quality of work of Scripps Research scientists in La Jolla and in Jupiter," said Scripps Research President Richard A. Lerner. "As we go forward, we will be able to leverage our expertise and our technology on both coasts to have the greatest impact on science and medicine worldwide."

Alan M. Krensky, director of the NIH Office of Portfolio Analysis and Strategic Initiatives, which oversees the Roadmap programs, said, "The Molecular Libraries program is the single largest investment of the Roadmap Initiative to date. It is a bold experiment to bring small molecule screening to academics. The impact on both interrogation of signaling pathways and the identification of lead compounds for drug development is expected to be transformative."

Scripps Research Professor Hugh Rosen, a faculty member on the La Jolla campus and the principal investigator on the project, said, "As an institution, Scripps Research produces the highest quality science through the synergistic blending of biology and chemistry. We have a unified approach in California and Florida, the same discipline, the same set of high standards in an integrated data environment. This very significant grant recognizes that combination of talent and technology that has successfully led to the discovery of proof-of-concept chemical probes of defined mechanism that work both in the test-tube and in vivo."

Professor Pat Griffin, chair of the Molecular Therapeutics Department and head of the Translational Research Institute at Scripps Florida, and the co-principal investigator, added, "We were one of ten institutions in the pilot phase of this project. Our accomplishments in La Jolla and Jupiter during that time have made us one of only four comprehensive centers in what is now the definitive phase. While we may be on two coasts, our core commitment has always been to work together as a unified team to produce the best science possible."

In addition to Rosen and Griffin, other key contributors include William Roush, Scripps Research professor and executive director of Medicinal Chemistry at Scripps Florida; Peter Hodder, co-principal investigator and science director for lead compound identification at Scripps Florida; Edward Roberts, professor, Medicinal Chemistry, and Benjamin Cravatt, professor and chair of Chemical Physiology, both in La Jolla.

Scripps Florida Impact

The new funding will have an impact on the ongoing research at Scripps Florida, according to Lerner.

"A significant portion of this grant will be coming to Scripps Florida," Lerner said. "So there will be a need for new people to match the scope of the project. That's in addition to the ongoing recruitment under way at all levels as we contemplate the move into our three new buildings in early 2009."

The new grant is seen as validation of the vision and decision to expand Scripps Research into Florida, according to Lerner.

"To have become a serious competitor for federal funding of biomedical research on such a large scale and in such a short period of time is recognition not only of the work of our scientists, but also of the wise investment by the people of Florida and Palm Beach County in building Scripps Florida in the first place," Lerner said.

The Beginning

The current initiative began in 2005 as a three-year pilot program, part of the National Institutes of Health Roadmap Initiative, a series of separate programs, many of which cross the traditional boundaries between the NIH's 27 institutes and centers. The Scripps Research pilot program, led by Hugh Rosen, received an initial grant of $10.4 million.

Scientists in the pilot projects have been using the Molecular Libraries Small Molecule Repository, a public collection of hundreds of thousands of chemically diverse small organic compounds that have the potential of interacting with various human proteins and other molecules involved in disease. The primary question is how—which compound will interact with which human target involved in which disease? Once the targets are identified, scientists can take the next step and work on finding ways to control or otherwise correct them.

"Since the pilot program started, our overall goals haven't changed—to discover and generate specific clinical tools that can help transform basic science into medicine," Griffin said. "This funding will allow us to expand the discovery of targets that can be identified as new points for therapeutic intervention. Our hope is to speed up the translation of our work into medical solutions that will one day help to improve the lives of people who are ill."

The pilot grant to Scripps Research was also a first to fund a variety of activities between the California and Florida campuses. Assays were developed in La Jolla, while high throughput screening was done in Jupiter, using state-of-the-art robotic systems. One robotic system, with the ability to test over one million assay wells per day and an on-line storage capacity of over a million compounds, is dedicated entirely to high throughput screening.

These automated assays, together with multiple secondary assays often combining chemical and genetic approaches then support medicinal chemistry efforts after a high throughput screening campaign is completed, allow scientists to rapidly prove the mechanism and defects in hits, and synthetically optimize them for proof-of-concept function. Chemistry is performed both in La Jolla and Jupiter, where chemists and biologists work side-by-side to advance chemical discovery. Publications and probes exemplifying the success of the Scripps Center can be found at http://molscreen.florida.scripps.edu/index.shtml.  More than 30 publications from the pilot phase of the center have been published and can be found at http://molscreen.florida.scripps.edu/publications.shtml.

Broad Approach

"Our work is not confined to a single disease or molecular class," Griffin pointed out. "We bring broad expertise and a range of activities to bear on this. We have the capability to undertake any compound class that's brought to the center by our own researchers and those from other institutions. This is really a lead candidate development funnel."

Since 2005, Scripps Research has reached full production capabilities for assay development and for ultra-high throughput screening of approximately two full chemical library assays per month. In the past 12 months alone, 27 ultra-high throughput screening campaigns were conducted for 18 molecular targets in eight different target classes, and using eight different detection formats.

"To date, the Scripps Florida HTS laboratory has worked with more than 35 state, national, and international collaborators on various projects, and conducted more than seven million individual tests on thousands of different compounds," Hodder said. "But this is more than just the screening process—it's really the starting point. We have reached a steady state production."

The grant funds will be administered jointly by the National Institute of Mental Health (NIMH) and the National Human Genome Research Institute (NHGRI) on behalf of the NIH.

Send comments to: mikaono[at]scripps.edu

"This is a tremendous accomplishment and validation of the quality of work of Scripps Research scientists in La Jolla and in Jupiter."

—Richard A. Lerner

The Stäubli RX130L robotic arm makes up part of Scripps Florida's state-of-the-art screening technologies.