| Autor: |
Lee OW; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Austin S; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Gamma M; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Cheff DM; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Lee TD; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Wilson KM; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Johnson J; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Travers J; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Braisted JC; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Guha R; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Klumpp-Thomas C; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Shen M; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA., Hall MD; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA. |
| Abstrakt: |
Cell-based phenotypic screening is a commonly used approach to discover biological pathways, novel drug targets, chemical probes, and high-quality hit-to-lead molecules. Many hits identified from high-throughput screening campaigns are ruled out through a series of follow-up potency, selectivity/specificity, and cytotoxicity assays. Prioritization of molecules with little or no cytotoxicity for downstream evaluation can influence the future direction of projects, so cytotoxicity profiling of screening libraries at an early stage is essential for increasing the likelihood of candidate success. In this study, we assessed the cell-based cytotoxicity of nearly 10,000 compounds in the National Institutes of Health, National Center for Advancing Translational Sciences annotated libraries and more than 100,000 compounds in a diversity library against four normal cell lines (HEK 293, NIH 3T3, CRL-7250, and HaCat) and one cancer cell line (KB 3-1, a HeLa subline). This large-scale library profiling was analyzed for overall screening outcomes, hit rates, pan-activity, and selectivity. For the annotated library, we also examined the primary targets and mechanistic pathways regularly associated with cell death. To our knowledge, this is the first study to use high-throughput screening to profile a large screening collection (>100,000 compounds) for cytotoxicity in both normal and cancer cell lines. The results generated here constitute a valuable resource for the scientific community and provide insight into the extent of cytotoxic compounds in screening libraries, allowing for the identification and avoidance of compounds with cytotoxicity during high-throughput screening campaigns. |
