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Linking phenotypes and modes of action through high-content screen fingerprints
Felix Reisen1, Amelie Sauty de Chalon1, Martin Pfeifer1
1Novartis Institutes for BioMedical Research , Center for Proteomic Chemistry, Basel, Switzerland .
Assay and Drug Development Technologies
|August 11, 2015
Summary
High-content screening (HCS) fingerprints reveal cellular phenotypes linked to drug targets and pathways. This method identified novel compound-target associations, including Silmitasertib
Area of Science:
- Cellular and molecular biology
- Pharmacology and drug discovery
- Bioinformatics and computational biology
Background:
- High-content screening (HCS) enables detailed monitoring of cellular responses to compounds.
- Cellular phenotypes, captured as multivariate image readouts (HCS fingerprints), serve as biological compound descriptors.
- Clustering HCS fingerprints can reveal similarities in compound targets and cellular pathways.
Purpose of the Study:
- To develop and validate an HCS-based profiling panel for characterizing compound mechanisms of action.
- To link cellular phenotypes observed via HCS to specific cellular processes and protein targets.
- To discover novel compound-target associations using HCS fingerprint clustering.
Main Methods:
- Developed an HCS profiling panel assessing phenotypic effects in six cellular compartments (nucleus, cytoplasm, ER, Golgi, cytoskeleton).
- Profiled 2,725 well-annotated compounds using the HCS panel.
- Clustered HCS fingerprints to identify relationships between cellular phenotypes, pathways, and targets.
Main Results:
- Clustering revealed distinct groups enriched for specific targets (e.g., HDAC, HSP90, TUB), pathways (e.g., PIK3/AKT/mTOR), and disease-associated gene sets (e.g., psoriasis, leukemia).
- Identified novel compound-target associations, notably the submicromolar inhibitory activity of Silmitasertib (casein kinase inhibitor) against PI3K and mTOR.
- Demonstrated the utility of HCS fingerprints for predicting compound biological activity and mechanism of action.
Conclusions:
- The developed HCS profiling panel effectively characterizes compound mechanisms of action by linking phenotypes to targets.
- HCS fingerprint-based clustering is a powerful approach for target identification and drug repurposing.
- This study successfully identified novel biological activities for known compounds, advancing drug discovery efforts.
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