Felix Reisen Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry
Amelie Sauty de Chalon Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry
Martin Pfeifer Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry
Xian Zhang Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry
Daniela Gabriel Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry
Paul Selzer Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry

The Use of High-Content Screening as a Powerful Technique for Monitoring Phenotypic Responses

In today's drug discovery campaigns we observe a clear trend toward more complex assay environments. While target-based high-throughput screening (HTS) still plays an important role, phenotypic screening techniques are gaining importance. Phenotypic screening assays are believed to be more closely linked to a given disease state than target-based approaches where the molecular hypothesis might not be relevant for disease pathogenesis.

One approach to phenotypic drug discovery is high-content screening (HCS), an HTS technique based on automated microscopy. HCS allows for highly multiplexed assay readouts that can be used to simultaneously assay several modes of action or toxicity. Additionally, HCS enables screening in a controlled and disease-relevant environment by even using patient-derived cell cultures.

While there are many advantages to phenotypic screening, additional knowledge about the targets being modulated to bring about the desired phenotype can be highly beneficial, for example, in lead optimization, by helping interpretation of structure activity relationships. In addition, knowledge of the target can also help to identify related targets that may bring about challenges in designing selective lead molecules.

Various techniques have been developed to support target identification for compounds active in phenotypic assays. These include approaches such as affinity chromatography, biochemical fractionation, radioactive ligand binding assays, drug affinity responsive target stability. Alternative approaches are based on in vivo chemical genomic assays developed in yeast Saccharomyces cerevisiae or in silico approaches using historic knowledge about compound target associations. In silico methods predict possible targets for a compound by comparing the similarity of the compound's profile (using chemical similarity, gene expression profile, or HCS experiments) to those of previously characterized compounds with known target.

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ASSAY & Drug Development Technologies, published by Mary Ann Liebert, Inc., offers a unique combination of original research and reports on the techniques and tools being used in cutting-edge drug development. GEN presents here one article "Linking Phenotypes and Modes of Action Through High-Content Screen Fingerprints." Authors of the paper are Felix Reisen, Amelie Sauty de Chalon, Martin Pfeifer, Xian Zhang, Daniela Gabriel, and Paul Selzer.

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