Enhanced selectivity screening of GPCR ligands using a label-free cell based assay technology

Drug discovery efforts advance in step with advancements in assay technologies, as new technologies provide new lenses through which biology can be viewed. The novel information gathered results in the better understanding of drug-target interactions leading to better decision making during the drug discovery process. One area of rapid development is within label-free technologies. Label-free technologies offer many distinct advantages to the drug discovery workflow. One such novel technology is the CellKey System, an impedance-based label-free live cell assay platform. The system is based on impedance technology and is a universal platform for the functional measurement of all classes of G-protein coupled receptors (GPCRs). Data are generated in a kinetic fashion on both endogenously expressed and transfected receptors in a wide variety of cell types. In the studies detailed here, we used the system to perform an enhanced selectivity screen of a small panel of compounds simultaneously against two unrelated GPCR targets signaling through different pathways. Utilizing both the quantitative measures of cellular activation and the qualitative information inherent in the rich output data, we gained knowledge not only about the relative selectivity of each compound across both targets, but also about the character of the interaction of each with the cellular target. In this manner, we successfully demonstrated proof of principal for using an impedance-based technology to perform selectivity analyses and to triage lead compounds in a simplified format.