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          Institute: MPI für molekulare Zellbiologie und Genetik     Collection: MPI-CBG Publications 2015 (arch)     Display Documents



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ID: 718064.0, MPI für molekulare Zellbiologie und Genetik / MPI-CBG Publications 2015 (arch)
A Combination of Screening and Computational Approaches for the Identification of Novel Compounds That Decrease Mast Cell Degranulation.
Authors:McShane, Marisa P.; Friedrichson, Tim; Giner, Angelika; Meyenhofer, Felix; Barsacchi, Rico; Bickle, Marc; Zerial, Marino
Date of Publication (YYYY-MM-DD):2015
Title of Journal:Journal of Biomolecular Screening
Volume:20
Issue / Number:6
Start Page:720
End Page:728
Copyright:not available
Audience:Experts Only
Intended Educational Use:No
Abstract / Description:High-content screening of compound libraries poses various challenges in the early steps in drug discovery such as gaining insights into the mode of action of the selected compounds. Here, we addressed these challenges by integrating two biological screens through bioinformatics and computational analysis. We screened a small-molecule library enriched in amphiphilic compounds in a degranulation assay in rat basophilic leukemia 2H3 (RBL-2H3) cells. The same library was rescreened in a high-content image-based endocytosis assay in HeLa cells. This assay was previously applied to a genome-wide RNAi screen that produced quantitative multiparametric phenotypic profiles for genes that directly or indirectly affect endocytosis. By correlating the endocytic profiles of the compounds with the genome-wide siRNA profiles, we identified candidate pathways that may be inhibited by the compounds. Among these, we focused on the Akt pathway and validated its inhibition in HeLa and RBL-2H3 cells. We further showed that the compounds inhibited the translocation of the Akt-PH domain to the plasma membrane. The approach performed here can be used to integrate chemical and functional genomics screens for investigating the mechanism of action of compounds.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Thüm
Affiliations:MPI für molekulare Zellbiologie und Genetik
Identifiers:LOCALID:6179
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