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Bioorthogonal Probes to study MDM2-p53 inhibitors in cells and to develop high content screening assays for drug discovery

D'Alessandro, Pier Luca and Furet, Pascal and Baysang, Frederic and Brunner, Reto and Vorherr, Thomas and Stachyra, Therese-Marie and Ottl, Johannes and Lizos, Dimitrios and Cobos-Correa, Amanda and Marzinzik, Andreas and Kaufmann, Markus (2016) Bioorthogonal Probes to study MDM2-p53 inhibitors in cells and to develop high content screening assays for drug discovery. Angewandte Chemie International Edition, 55 (52). pp. 16026-16030. ISSN 1433-7851

Abstract

To study the behavior of MDM2-p53 inhibitors in a disease-relevant cellular model, we have developed and validated a set of bioorthogonal probes that can be fluorescently labeled in cells and used in high content screening assays. Using automated image analysis and single cell resolution, we could visualize the intracellular target binding of compounds by co-localization and quantify target upregulation upon MDM2-p53 inhibition in an osteosarcoma model. In addition, we developed a high throughput assay to quantify target occupancy of non-tagged MDM2-p53 inhibitors by competition and to identify novel chemical matter. This approach could be expanded to other targets for lead discovery applications.

Item Type: Article
Keywords: biorthogonal probe • high content imaging • MDM2 • target engagement • fluorescent tags
Date Deposited: 04 Jan 2017 00:45
Last Modified: 04 Jan 2017 00:45
URI: https://oak.novartis.com/id/eprint/31182

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