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Nov 15, 2009 (Vol. 29, No. 20)

Strategies for Companies Targeting GPCRs

Emerging Tools and Methodologies for Screening and Discovery Are Improving Odds for Success

  • Sidebar: Examining Compound Selectivity and Specificity

    At Cambridge Healthtech’s “Discovery on Target” meeting, Blaine Armbruster, Ph.D., manager, GPCR drug discovery, Millipore, gave a talk on “Testing the Hypothesis of Allosteric Compound Selectivity through Large Scale Selectivity Profiling.”

    Compound specificity (whether a compound interacts with unintended protein targets) is always a concern for drug safety and, therefore, is a prominent issue for drug development. GPCR compounds are no exception and certain off-target interactions contribute to the adverse reactions of marketed compounds.

  • Making an Assumption

    The lack of selectivity has been attributed to the high degree of conservation of orthosteric binding sites, noted Dr. Armbruster.

    “An assumption has been made that allosteric compounds, i.e., compounds that interact with less conserved, nonorthosteric sites, may have promise as more selective compounds,” he said. “However, we conducted a study that profiled kinase inhibitors through a large panel of GPCRs via Millipore’s GPCRProfiler® service. We demonstrated that these compounds can functionally interact with some GPCRs.”

    The data highlights the inherent challenge that GPCRs present for compound selectivity, regardless of whether or not a compound was primarily designed for a GPCR target, added Dr. Armbruster.

    He explained that Millipore has developed a service, AllostericProfiler, that tests the selectivity of both orthosteric and allosteric compounds at over 155 different GPCRs.

    “The design of AllostericProfiler, which can detect three different activities (agonist, antagonist/NAM, and PAM activity) was applied to two different compounds from Jeffrey Conn’s lab at Vanderbilt University. Of the 30 receptors interrogated, the compounds were found to have PAM activity at a specific acetylcholine muscarinic receptor.

    However, the screen reportedly also revealed a potential off-target agonist activity for one of the compounds at a bombesin receptor. “This suggests that, while family-specific selectivity may be enhanced for allosteric compounds, general selectivity across a diverse collection of GPCRs may still be a concern,” pointed out Dr. Armbruster. 


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