Virtual Screening-Based Discovery and Mechanistic Characterization of the Acylthiourea MRT-10 Family as Smoothened Antagonists

The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental...

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Bibliographic Details
Published in:Molecular pharmacology 2010-10, Vol.78 (4), p.658-665
Main Authors: Manetti, Fabrizio, Faure, Helene, Roudaut, Hermine, Gorojankina, Tatiana, Traiffort, Elisabeth, Schoenfelder, Angele, Mann, Andre, Solinas, Antonio, Taddei, Maurizio, Ruat, Martial
Format: Article
Language:English
Subjects:
Animals
Cell Line
Drug Discovery - methods
Drug Evaluation, Preclinical - methods
Humans
Libraries, Digital
Life Sciences
Mice
Mice, Inbred C3H
Neurons and Cognition
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - physiology
Smoothened Receptor
Thiourea - chemistry
Thiourea - metabolism
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Summary:The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated and validated a pharmacophoric model for Smo inhibitors constituted by three hydrogen bond acceptor groups and three hydrophobic regions. We used this model for the virtual screening of a library of commercially available compounds. Visual and structural criteria allowed the selection of 20 top scoring ligands, and an acylthiourea, N-(3-benzamidophenylcarbamothioyl)-3,4,5-trimethoxybenzamide (MRT-10), was identified and characterized as a Smo antagonist. The corresponding acylurea, N-(3-benzamidophenylcarbamoyl)-3,4,5-trimethoxybenzamide (MRT-14), was synthesized and shown to display, in various Hh assays, an inhibitory potency comparable to or greater than that of reference Smo antagonists cyclopamine and N-((3S,5S)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)-N-(3-methoxybenzyl)-3,3-dimethylbutanamide (Cur61414). Focused virtual screening of the same library further identified five additional related antagonists. MRT-10 and MRT-14 constitute the first members of novel families of Smo antagonists. The described virtual screening approach is aimed at identifying novel modulators of Smo and of other G-protein coupled receptors.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.110.065102