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- Title
Discovery of a Novel Inhibitor of the Hedgehog Signaling Pathway through Cell-based Compound Discovery and Target Prediction.
- Authors
Kremer, Lea; Schultz‐Fademrecht, Carsten; Baumann, Matthias; Habenberger, Peter; Choidas, Axel; Klebl, Bert; Kordes, Susanne; Schöler, Hans R.; Sterneckert, Jared; Ziegler, Slava; Schneider, Gisbert; Waldmann, Herbert
- Abstract
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.
- Subjects
PROTEOMICS; BIOACTIVE compounds; CHEMINFORMATICS; PYRAZOLONES; MEDULLOBLASTOMA
- Publication
Angewandte Chemie, 2017, Vol 129, Issue 42, p13201
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201707394