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Linking phenotypes and mode of action through high content screening fingerprints

Reisen, Felix and Sauty De Chalon, Amelie and Pfeifer, Martin and Zhang, Xian and Gabriel, Daniela and Selzer, Paul (2015) Linking phenotypes and mode of action through high content screening fingerprints. Linking phenotypes and mode of action through high content screening fingerprints, 13 (7). pp. 415-427. ISSN 1540-658X1557-8127

Abstract

High content screening (HCS) is a powerful technique for monitoring phenotypic responses to compound treatment on a cellular and sub-cellular level. Cellular phenotypes can be characterized by multivariate image readouts such as shape, intensity or texture. The corresponding feature vectors can thus be defined as HCS-fingerprints that serve as a powerful biological compound descriptor. Therefore clustering of HCS-fingerprints across compound treatments allows for the identification of similarities in protein targets or pathways. We developed an HCS¬-based profiling panel that serves as basis for characterizing the mode of action of compounds. This panel measures phenotypic effects in six different compartments of U2-OS cells, namely the nucleus, the cytoplasm, the endoplasmic reticulum, the Golgi apparatus and the cytoskeleton. We profiled a set of 2’725 well-annotated compounds and clustered their corresponding HCS-fingerprints to establish links between predominant cellular phenotypes and cellular processes and protein targets. We found various different clusters enriched for individual targets (e.g. HDAC, HSP90, TOP1, HMGCR, TUB), signaling pathways (e.g. PIK3/AKT/mTOR), or gene sets associated with diseases (e.g. psoriasis, leukemia). Based on this clustering we were able to identify novel compound target associations for selected compounds such as a sub micromolar inhibitory activity of Silmitasertib on PI3K and mTOR.

Item Type: Article
Keywords: high content screening, HCS-fingerprints, multi-parametric data, phenotypic assays, phenotypes
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/23192

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