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Scripps researchers make metabolic breakthrough

Normally, this kind of story would be something you’d see in the “Bench Press” portion of our e-newsletter or website (click here) but in this post-Thanksgiving season, our cornucopia of stories was overflowing a bit, and I hate to throw out perfectly tasty and still-fresh leftovers, so enjoy this bit of research news right here at the blog.

Scripps researchers’ synthetic agonist of hormone-mediating proteins could yield treatments for metabolic disorders

By Amy Swinderman

JUPITER, Fla.—Scientists at the Scripps Research Institute have discovered the first synthetic agonist of retinoid-related orphan (ROR) nuclear receptor, protein molecules that mediate hormone activity inside the cell. Publishing their discovery in the November issue of the journal ACS Chemical Biology, the scientists say their finding could pave the way for the development of a therapeutic compound to treat numerous metabolic disorders and even cancer.

The lead author of the study, Dr. Thomas Burris, a professor in the Department of Molecular Therapeutics at Scripps’ Florida campus, and his colleagues have for years focused on nuclear pharmacology and chemical biology, and in particular have been investigating orphan receptors of the nuclear receptor (NR) superfamily. Members of the NR superfamily display a conserved domain structure with highly conserved DNA-binding and ligand-binding domains, and include the receptors for the steroid hormone, thyroid hormone and bile acids and oxysterols. Although many of the 48 NRs found in the human are characterized as ligand-activated transcription factors, a significant number of these proteins still have uncharacterized ligands.

The retinoic acid receptor-related orphan receptors RORα and RORγ are two of these orphan receptors that have been demonstrated to play important roles in regulation of metabolism and immune function. Last year, Burris and his colleagues identified a high-affinity synthetic inverse agonist of this same pair of nuclear receptors.

For this new study, the researchers extended that discovery with the identification of the compound T1317, as a molecular scaffold to synthesize an array of compounds and assess their activity against a number of receptors, including RORα and RORγ. 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.

The agonist, a compound known as T1317, is a molecular scaffold to synthesize an array of compounds and assess their activity against a number of receptors, including RORα and RORγ. For this study, the Scripps researchers describe the identification of a synthetic RORα and RORγ ligand, SR1078. SR1078 modulates the conformation of

RORγ in a biochemical assay and activates RORα and RORγ driven transcription.

“Pharmacokinetic studies indicate that SR1078 displays reasonable exposure following injection into mice, and consistent with SR1078 functioning as a RORα/RORγ agonist, expression of two ROR target genes, glucose-6-phosphatase and fibroblast growth factor 21, were stimulated in the liver,” Burris says. “Thus, we have identified the first synthetic RORα/RORγ agonist, and this compound can be utilized as a chemical tool to probe the function of these receptors both in vitro and in vivo.”

Those properties, Burris says, give SR1078 potential as a possible therapeutic compound for many different metabolic disorders. Nuclear receptors have become drug development targets for diseases like type 2 diabetes, atherosclerosis and metabolic syndrome, and have also been implicated in the progress of a number of cancers.

However, Burris cautions that this was a proof-of-principle study, and additional experiments are needed to examine the pharmacological profile of this compound in vivo.

“We’re certainly interested in merging the academic side of this with the drug development side,” says Burris, who spent 10 years working for pharmaceutical companies Johnson & Johnson and Eli Lilly & Co. “We’re still looking around for folks who will take it further, because of course on the academic side, we can only take it so far.”

The first author of the study, “Identification of SR1078, a Synthetic Agonist for the Orphan Nuclear Receptors RORα and RORγ,” was Yongjun Wang. Others authors include Naresh Kumar, Philippe Nuhant, Michael D. Cameron, Monica A. Istrate, William R. Roush and Patrick R. Griffin. The study was supported by the National Institutes of Health.

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December 8, 2010 - Posted by | Academia & Non-Profit, Labwork & Science

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