Rapid Structure-Activity and Selectivity Analysis of Kinase Inhibitors by BioMAP Analysis in Complex Human Primary Cell-Based Models
| Autor: | Evangelos Hytopoulos, Eric J. Kunkel, Eugene C. Butcher, Dat Nguyen, Anthony C. Bishop, Ivan Plavec, Raynard L. Bateman, Leon T. Kao, Yuker Wang, Elen S. Rosler, Jennifer Melrose, Kevan M. Shokat, Ellen L. Berg |
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| Rok vydání: | 2004 |
| Předmět: |
p38 mitogen-activated protein kinases
Inflammation Biology Transfection Peripheral blood mononuclear cell Structure-Activity Relationship Drug Delivery Systems Immune system Drug Discovery medicine Animals Humans RNA Small Interfering Protein kinase A Protein Kinase Inhibitors Cells Cultured Kinase Gene Expression Profiling Cell biology Electroporation Molecular Medicine Endothelium Vascular Signal transduction medicine.symptom Protein Kinases Function (biology) |
| Zdroj: | ASSAY and Drug Development Technologies. 2:431-442 |
| ISSN: | 1557-8127 1540-658X |
| DOI: | 10.1089/adt.2004.2.431 |
| Popis: | Rapid, quantitative methods for characterizing the biological activities of kinase inhibitors in complex human cell systems could allow the biological consequences of differential target selectivity to be monitored early in development, improving the selection of drug candidates. We have previously shown that Biologically Multiplexed Activity Profiling (BioMAP) permits rapid characterization of drug function based on statistical analysis of protein expression data sets from complex primary human cellbased models of disease biology. Here, using four such model systems containing primary human endothelial cells and peripheral blood mononuclear cells in which multiple signaling pathways relevant to inflammation and immune responses are simultaneously activated, we demonstrate that BioMAP analysis can detect and distinguish a wide range of inhibitors directed against different kinase targets. Using a panel of p38 mitogen-activated protein kinase antagonists as a test set, we show further that related compounds can be distinguished by unique features of the biological responses they induce in complex systems, and can be classified according to their induction of shared (on-target) and secondary activities. Statistical comparisons of quantitative BioMAP profiles and analysis of profile features allow correlation of induced biological effects with chemical structure and mapping of biological responses to chemical series or substituents on a common scaffold. Integration of automated BioMAP analysis for prioritization of hits and for structure-activity relationship studies may improve and accelerate the design and selection of optimal therapeutic candidates. |
| Databáze: | OpenAIRE |
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