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Research ArticleArticle

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

Fabrizio Manetti, Helene Faure, Hermine Roudaut, Tatiana Gorojankina, Elisabeth Traiffort, Angele Schoenfelder, Andre Mann, Antonio Solinas, Maurizio Taddei and Martial Ruat
Molecular Pharmacology October 2010, 78 (4) 658-665; DOI: https://doi.org/10.1124/mol.110.065102
Fabrizio Manetti
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Helene Faure
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Hermine Roudaut
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Tatiana Gorojankina
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Elisabeth Traiffort
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Angele Schoenfelder
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Andre Mann
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Antonio Solinas
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Maurizio Taddei
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Martial Ruat
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Abstract

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.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by La Ligue contre le Cancer (Comité des Yvelines); l'Institut National du Cancer; l'Association pour la Recherche contre le Cancer [Grant 3850], l'Association Française contre les Myopathies [Grant 12181]; the French Agence Nationale de la Recherche [Grant 07-physio-010-04]; and The Neuropole de Recherche Francilien [Doctoral Fellowship 248890].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.065102.

  • ABBREVIATIONS:

    Hh
    Hedgehog
    Ptc
    Patched
    GPCR
    G protein-coupled receptor
    Smo
    Smoothened
    BCC
    basal cell carcinoma
    Cur61414
    N-((3S,5S)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)-N-(3-methoxybenzyl)-3,3-dimethylbutanamide
    Z″″
    N-(4-chloro-3-(6-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide
    SAG
    Smoothened agonist
    DMSO
    dimethyl sulfoxide
    HEK
    human embryonic kidney
    IP
    inositol phosphates
    ShhN
    N-terminal fragment of human Sonic hedgehog
    AP
    alkaline phosphatase
    PBS
    phosphate-buffered saline
    DAPI
    4,6-diamidino-2-phenylindole
    BC
    Bodipy-cyclopamine
    HBA
    hydrogen-bond acceptor
    HY
    hydrophobic
    MRT-24
    N-(3-benzamidophenylcarbamothioyl)-3,4-dimethoxybenzamide
    MRT-29
    4-methoxy-N-(3-(2-methylbenzamido)phenylcarbamothioyl)-3-nitrobenzamide
    MRT-31
    N-(3-(3-biphenylcarbonylthioureido)phenyl)furan-2-carboxamide
    MRT-39
    N-(3-(3-(3,4-dimethoxybenzoyl)thioureido)phenyl)furan-2-carboxamide
    MRT-42
    N-(5-(benzo[d]thiazol-2-yl)-2-methylphenylcarbamothioyl)-3,4-dimethoxybenzamide.

  • Received March 26, 2010.
  • Accepted July 27, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
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Research ArticleArticle

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

Fabrizio Manetti, Helene Faure, Hermine Roudaut, Tatiana Gorojankina, Elisabeth Traiffort, Angele Schoenfelder, Andre Mann, Antonio Solinas, Maurizio Taddei and Martial Ruat
Molecular Pharmacology October 1, 2010, 78 (4) 658-665; DOI: https://doi.org/10.1124/mol.110.065102

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Research ArticleArticle

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

Fabrizio Manetti, Helene Faure, Hermine Roudaut, Tatiana Gorojankina, Elisabeth Traiffort, Angele Schoenfelder, Andre Mann, Antonio Solinas, Maurizio Taddei and Martial Ruat
Molecular Pharmacology October 1, 2010, 78 (4) 658-665; DOI: https://doi.org/10.1124/mol.110.065102
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