Articles | Volume 2, issue 1
https://doi.org/10.5194/mr-2-355-2021
© Author(s) 2021. This work is distributed under
the Creative Commons Attribution 4.0 License.
the Creative Commons Attribution 4.0 License.
Special issue:
https://doi.org/10.5194/mr-2-355-2021
© Author(s) 2021. This work is distributed under
the Creative Commons Attribution 4.0 License.
the Creative Commons Attribution 4.0 License.
Research article
| 
02 Jun 2021
Research article |
| 02 Jun 2021
| 02 Jun 2021
Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling
Nestor Kamdem
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
Yvette Roske
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Dmytro Kovalskyy
Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine
ChemBio Ctr, Taras Shevchenko National University of Kyiv, 62 Volodymyrska, Kyiv 01033, Ukraine
Maxim O. Platonov
Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine
ChemBio Ctr, Taras Shevchenko National University of Kyiv, 62 Volodymyrska, Kyiv 01033, Ukraine
Oleksii Balinskyi
Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine
ChemBio Ctr, Taras Shevchenko National University of Kyiv, 62 Volodymyrska, Kyiv 01033, Ukraine
Annika Kreuchwig
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
Jörn Saupe
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
Liang Fang
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Anne Diehl
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Peter Schmieder
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Gerd Krause
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Jörg Rademann
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Straße 2 + 4, 14195 Berlin, Germany
Udo Heinemann
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Walter Birchmeier
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Hartmut Oschkinat
CORRESPONDING AUTHOR
Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
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Cited
7 citations as recorded by crossref.
- Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer C. Nardella et al. 10.1186/s13062-021-00303-9
- Anticancer Activity of (S)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-oxo-1-((pyridin-4-ylmethyl)amino)propan-2-yl)-1H-indole-2-carboxamide (RS4690), a New Dishevelled 1 Inhibitor A. Coluccia et al. 10.3390/cancers14051358
- Targeting peptide‐mediated interactions in omics J. Lin et al. 10.1002/pmic.202200175
- Structural and Functional Insights into Dishevelled-Mediated Wnt Signaling L. Wang et al. 10.3390/cells13221870
- Small-molecule inhibitors of WNT signalling in cancer therapy and their links to autophagy and apoptosis N. Menon et al. 10.1016/j.ejphar.2024.177137
- Targeting Wnt Pathways with Small Molecules as New Approach in Cardiovascular Disease S. Mousavi et al. 10.2174/011573403X333038241023153349
- Exploiting the Carboxylate-Binding Pocket of β-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library S. Park et al. 10.1021/acs.jmedchem.3c01834
7 citations as recorded by crossref.
- Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer C. Nardella et al. 10.1186/s13062-021-00303-9
- Anticancer Activity of (S)-5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-oxo-1-((pyridin-4-ylmethyl)amino)propan-2-yl)-1H-indole-2-carboxamide (RS4690), a New Dishevelled 1 Inhibitor A. Coluccia et al. 10.3390/cancers14051358
- Targeting peptide‐mediated interactions in omics J. Lin et al. 10.1002/pmic.202200175
- Structural and Functional Insights into Dishevelled-Mediated Wnt Signaling L. Wang et al. 10.3390/cells13221870
- Small-molecule inhibitors of WNT signalling in cancer therapy and their links to autophagy and apoptosis N. Menon et al. 10.1016/j.ejphar.2024.177137
- Targeting Wnt Pathways with Small Molecules as New Approach in Cardiovascular Disease S. Mousavi et al. 10.2174/011573403X333038241023153349
- Exploiting the Carboxylate-Binding Pocket of β-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library S. Park et al. 10.1021/acs.jmedchem.3c01834
Latest update: 10 Jul 2025
Short summary
The Wnt signalling pathway plays a major role in prevention of cancer, whereby the protein Dishevelled connects from the transmembrane receptor Frizzled to downstream effectors via its PDZ domain. Here, cycles of chemical synthesis and structural biology are applied to develop PDZ ligands that block the Frizzled–Dishevelled interaction using NMR for screening, in ligand development, and for deriving structure–activity relationships. Cellular reporter assays demonstrate their efficacy.
The Wnt signalling pathway plays a major role in prevention of cancer, whereby the protein...
Special issue