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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2018 (publ. 2017, arch)     Display Documents

ID: 744133.0, MPI für molekulare Biomedizin / Jahrbuch 2018 (publ. 2017, arch)
Discovery of a Novel Inhibitor of the Hedgehog Signaling Pathway through Cell-based Compound Discovery and Target Prediction
Authors:Kremer, L.; Schultz-Fademrecht, C.; Baumann, M.; Habenberger, P.; Choidas, A.; Klebl, B.; Kordes, S.; Scholer, H. R.; Sterneckert, J.; Ziegler, S.; Schneider, G.; Waldmann, H.
Date of Publication (YYYY-MM-DD):2017-10-09
Title of Journal:Angew Chem Int ed Engl
Issue / Number:42
Start Page:13021
End Page:13025
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Cell-based assays enable monitoring of small-molecule bioactivity in a target-agnostic manner and help uncover new biological mechanisms. Subsequent identification and validation of the small-molecule targets, typically employing proteomics techniques, is very challenging and limited, in particular if the targets are membrane proteins. Herein, we demonstrate that the combination of cell-based bioactive-compound discovery with cheminformatic target prediction may provide an efficient approach to accelerate the process and render target identification and validation more efficient. Using a cell-based assay, we identified the pyrazolo-imidazole smoothib as a new inhibitor of hedgehog (Hh) signaling and an antagonist of the protein smoothened (SMO) with a novel chemotype. Smoothib targets the heptahelical bundle of SMO, prevents its ciliary localization, reduces the expression of Hh target genes, and suppresses the growth of Ptch(+/-) medulloblastoma cells.
Free Keywords:chemoinformatics; hedgehog signaling; inhibitors; target identification; target prediction
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:MPI für molekulare Biomedizin
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Fakultat fur Chemie und Chemische Biologie, Technische Universitat Dortmund, Otto-Hahn-Strasse 6, 44227, Dortmund, Germany. Lead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227, Dortmund, Germany. Abteilung Zell- und Entwicklungsbiologie, Max-Planck-Institut fur Molekulare Biomedizin, Rontgenstrasse 20, 48149, Munster, Germany. DFG-Center for Regenerative Therapies, Cluster of Excellence, Technische Universitat Dresden, Fetscherstr. 105, 01307, Dresden, Germany. Institut fur Pharmazeutische Wissenschaften, Departement Chemie und Angewandte Biowissenschaften, ETH Zurich, Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.
Identifiers:ISSN:1521-3773 (Electronic) 1433-7851 (Linking) %R 10.1... [ID No:1]
URL:https://www.ncbi.nlm.nih.gov/pubmed/28833911 [ID No:2]
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