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Scripps Research scientists identify first synthetic activator of 2 critical proteins

Discovery could produce new approaches to treat numerous metabolic disorders

Scientists from the Florida campus of The Scripps Research Institute have identified a novel synthetic activator of a pair of proteins that belong to a protein family playing key roles in human metabolism and immune function. The discovery could provide new and potentially more effective therapeutic approaches to diseases ranging from diabetes to osteoporosis.

The study was published in the November issue (Volume 5, Issue 11) of the journal ACS Chemical Biology.

"This new compound is particularly important because it works in vivo, and it is selective for certain receptors," said Tom Burris, a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. "These two properties give it significant potential as a possible therapeutic compound."

The new discovery represents the very first synthetic ligand (binding partner) that functions as an agonist (activator) of retinoid-related orphan (ROR) nuclear receptor. Nuclear receptors are protein molecules that mediate hormone activity inside the cell; they have been implicated in the progress of a number of cancers, and have also become drug development targets for diseases including type 2 diabetes, atherosclerosis, and metabolic syndrome.

Although scientists don't know the full therapeutic significance of the new synthetic ligand, its potential usefulness is clear, Burris noted.

"For example, loss of RORá in animal models renders them resistant to weight gain," he said, "while RORã has been shown to be involved in development of cells that are implicated in autoimmune diseases – and loss of RORã results in animals that are resistant to these types of disease."

RORá has also been shown to be required for normal bone development; animal models lacking this receptor develop osteoporosis, strongly suggesting that RORá agonists may have potential as a treatment of this disease. Osteoporosis affects as many as 44 million Americans, according to the National Institutes of Health. Burris and his colleagues also discovered a pathway stimulating liver secretion of FGF21—which has been shown to treat diabetic animals—via activation of ROR. Diabetes is estimated to affect 23.6 million Americans, according to the National Institutes of Health.

Second Major Discovery

This new agonist is the second that Burris and his Scripps Florida colleagues have identified.

In 2009, Burris and Patrick R. Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida, identified a high affinity synthetic inverse agonist of this same pair of nuclear receptors. An inverse agonist, which binds to the same site as an agonist, induces the opposite action of an agonist of that receptor.

For this new study, Burris said they used that first discovery, a compound known as T1317, as a molecular scaffold to synthesize an array of compounds and assess their activity against a number of receptors, including RORá and RORã.

The one compound that stood out was SR1078, which displayed a unique pharmacological profile that indicated it had a high potential for use as a chemical probe for assessing ROR receptor function in general.

"Unexpectedly, we found that SR1078 functioned as a ROR agonist," Burris said. "When we treated cells with SR1078 we got a significant increase in RORá transcription. Similarly, with RORã, SR1078 treatment resulted in a stimulation of RORã dependent transcription activity. Basically, it produced more of these receptor proteins, significantly so."

The first author of the study, "Identification of SR1078, a Synthetic Agonist for the Orphan Nuclear Receptors RORá and RORã," is Yongjun Wang of Scripps Research. Others authors include Naresh Kumar, Philippe Nuhant, Michael D. Cameron, Monica A. Istrate, William R. Roush, and Patrick R. Griffin, also of Scripps Research. For more information on the study, see

The study was supported by the National Institutes of Health.

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. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, Scripps Research currently employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Headquartered in La Jolla, California, the institute also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida. For more information, see

Mika Ono | EurekAlert!
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