Although 40% of all marketed drugs are targeted to G-protein coupled receptors (GPCRs), the similarity of GPCR binding sites coupled with saturated intellectual property around this chemical space have hampered GPCR drug discovery efforts. Increasingly, drug makers are instead focusing on novel allosteric GPCR sites to open up new chemical spaces. (Allosteric GPCR binding sites modulate native ligand binding sites and are potentially more specific.)
Facilitating the research of allosteric sites, Millipore’s AllostericProfiler™ service is the first to provide drug developers with cell-based assays to evaluate the functional selectivity of drugs against GPCRs.
“Allosteric modulators of GPCRs provide exciting new opportunities to discover and develop selective activators and inhibitors of GPCRs that have proven intractable when targeting orthosteric sites,” said Dr. Jeffrey Conn, Director of the Vanderbilt Program in Drug Discovery within the Department of Pharmacology at the Vanderbilt University Medical Center. “Our new understanding of allosteric modulation of GPCRs forces a shift in our thinking about approaches to panel screening for selectivity of novel agents and suggests that it is critical to employ functional panel screens of GPCR selectivity rather than relying exclusively on radioligand binding,” Conn added.
Millipore’s AllostericProfiler service allows researchers to screen the selectivity of their allosteric compounds for over 150 different GPCRs. Millipore can also provide custom services (AllostericScreener™ service) to help researchers identify new positive allosteric modulators for a GPCR target of interest.
By using a unique two-step addition protocol, the AllostericProfiler service detects both orthosteric compounds (which bind the native site) as well as allosteric modulators. First, the test compound is added to cells stably expressing a GPCR to determine whether the compound has agonist activity. Second, a dose response of a reference agonist, typically the native ligand, is added in the presence or absence of the test compound to compare how the test compound changes the reference agonist’s potency and efficacy. These changes can reveal activities ranging from positive to negative allosteric modulation.
“The search for druggable allosteric sites on GPCRs has begun in earnest,” observed Blaine Armbruster, Millipore Product Manager for GPCR Drug Discovery. “The therapeutics Cinacalcet (for hyperparathyroidism) and Maraviroc (for HIV) are both allosteric GPCR modulators and more GPCR-modulating drugs are in development.” The AllostericProfiler service is the latest addition to Millipore’s GPCRProfiler® service offering, which was launched by Millipore in 2006 as the first outsourced cell-based functional assay service for GPCR profiling using Millipore’s robust ChemiScreen™ GPCR cell lines.
About Millipore: Millipore (NYSE: MIL) is a Life Science leader providing cutting-edge technologies, tools, and services for bioscience research and biopharmaceutical manufacturing. As a strategic partner, we collaborate with customers to confront the world’s challenging human health issues. From research to development to production, our scientific expertise and innovative solutions help customers tackle their most complex problems and achieve their goals. Millipore Corporation is an S&P 500 company with more than 5,900 employees worldwide. For more information, please contact Millipore Tech Service at 1-800-548-7853 or 951-676-8080 or visit www.millipore.com.