JUPITER, FL, December 17, 2009 – The National Institutes of Health has awarded a three-year grant of more than $1.2 million to The Scripps Research Institute to develop a series of high-throughput screening tests that will help speed the discovery of potential small molecule therapies for breast cancer and cardiovascular disease.
Patrick Griffin, chair of the Scripps Research Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida, will lead the project as principal investigator. The grant will begin in January 2010.
The tests will focus on identifying ligands for the orphan nuclear receptor liver receptor homolog-1 or LRH-1, which plays a crucial role in hormone-driven breast cancer through its regulation of genes involved in hormone biosynthesis as well as fat and cholesterol metabolism – key risk factors in cardiovascular disease. Receptors like LRH-1 detect circulating signaling molecules (known as ligands) such as hormones or neurotransmitters; the ligand binds to the receptor, creating a biological response or blocking the receptor.
"Our goal is to uncover small molecules—either agonists or inverse agonists—that can be used to modulate or alter the activity of this important receptor," Griffin said. "Right now, there are no potent in vivo active LRH-1 agonists and no reports of any inverse agonists. Obviously, we need to better understand the function of this important receptor and its role in diseases like breast cancer if we're going to development new treatments. To do that, first we need to accelerate the identification of chemical probes."
The functions of agonists and antagonists are well known—a compound that activates a receptor is an agonist and one that blocks it is an antagonist. But an inverse agonist, which binds to same site as an agonist, induces the opposite action of an agonist of that receptor.
Griffin has long maintained an interest in nuclear receptors.
"There has been a lot of interest in nuclear receptors like LRH-1 and the RORs [retinoic acid receptor-related orphan receptors] because they play separate but overlapping roles in many important biological processes which make them ideal targets for the development of therapies for a wide range of disease," Griffin said. "Even though researchers in the field have characterized all 48 known human nuclear receptors, we're still looking for ligands for a number of them and, better still, more potent and more selective ligands. That's what our work with LRH-1 will accomplish."
Eventually, Griffin said, the development of modulators for LRH-1 will fall under the Scripps Research Institute Molecular Screening Center (SRIMSC), part of a collaborative effort among teams of scientists at the Scripps Research California and Florida campuses, which includes Griffin as a co-principal investigator. The center employs assay development at both campuses, high-throughput robotics to screen large chemical libraries in Florida, and chemistry at both campuses to develop high quality chemical probes. The center is one of only four such large centers nationwide and was awarded more than $80 million by the National Institutes of Health in 2008 to expand its work.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.