Vanderbilt University has signed a collaboration agreement with GlaxoSmithKline (GSK) for the discovery, development and commercialization of novel therapies for severe obesity.
The target is the melanocortin-4 receptor (MC4-R), which is involved in energy homeostasis, the balance of food intake and energy expenditure, and in the regulation of body weight. Defective melanocortin signaling is the most common cause of severe, early-onset obesity.
With major support from the National Institutes of Health (NIH), Roger Cone, Ph.D., and colleagues at Vanderbilt have identified a series of drug-like compounds, called positive allosteric modulators or PAMs, that “gently increase” MC4-R activity.
Under the collaboration agreement, Vanderbilt will do the pharmacology and pre-clinical testing, while GSK scientists will try to develop chemically similar compounds with improved activity and efficacy. The goal is to begin phase-1 testing in humans within three years — in 2016.
“It’s a very aggressive timeline,” said Cone, Joe C. Davis Chair in Biomedical Science and chair of the Department of Molecular Physiology and Biophysics, who discovered MC4-R and demonstrated its potential for treating obesity in the late 1990s.
“The power of the high throughput screening resources here at Vanderbilt has allowed us to find quality small molecule hits that can go directly into the drug development pipeline,” he said. “GSK has already put an outstanding team of chemists on the project, so I’m hopeful we may meet that timeline.”
The agreement with Vanderbilt is the second GSK has signed with a U.S. institution under its Discovery Partnerships with Academia (DPAc) program. Launched in 2011, the program joins the insight and creativity of academic scientists with GSK’s drug discovery expertise to develop innovative medicines.
“The DPAc program allows both GSK and Vanderbilt to do what they do best,” said Pearl Huang, Ph.D., vice president, DPAc. “We will combine Roger Cone’s knowledge of MC4-R with GSK’s experience in drug discovery and development to collaborate on treatments for a serious global healthcare problem.”
Up to 5 percent of cases of severe, early-onset obesity have been linked to heterozygous mutations in MC4-R that reduce melanocortin signaling by less than 50 percent of normal levels. Clinical trials of drugs that directly activated every MC4 receptor throughout the brain were not successful, however, because some individuals experienced a rise in blood pressure.
In comparison, PAMs act indirectly, to “boost” only those receptors that already being turned on by a native hormone. “Rather than activating all the receptors everywhere all the time, we just want to gently increase receptor activity two-fold,” Cone said.
This approach should avoid raising blood pressure in patients with partially defective melanocortin signaling, and may be effective in treating common obesity, as well, he added.
Cone credited the High Throughput Screening Facility in the Vanderbilt Institute of Chemical Biology and David Weaver, Ph.D., assistant professor of Pharmacology, with making his research possible. A rapid, robot-assisted screen of Vanderbilt’s “library” of 160,000 compounds led to the identification of “hit” compounds that act on the receptor.
The project was launched by Jacques Pantel, Ph.D., now at the French National Institute of Health and Medical Research in Paris. Postdoctoral fellow Julien Sebag, Ph.D., then led the screen with the assistance of lab manager Savannah Williams, primary research assistant for the project.
Under the terms of the agreement, GSK will provide research support to Vanderbilt for three years, additional payments for meeting project milestones and a share of royalties. Cone’s lab will continue research on the receptor supported by NIH grant DK070332.
