Small-molecule inhibitors of the PDZ domain of Dishevelled proteins interrupt Wnt signalling.

Autor:	Kamdem N; 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., Roske Y; Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany., Kovalskyy D; Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine.; ChemBio Ctr, Taras Shevchenko National University of Kyiv, 62 Volodymyrska, Kyiv 01033, Ukraine., Platonov MO; Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine.; ChemBio Ctr, Taras Shevchenko National University of Kyiv, 62 Volodymyrska, Kyiv 01033, Ukraine., Balinskyi O; Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine.; ChemBio Ctr, Taras Shevchenko National University of Kyiv, 62 Volodymyrska, Kyiv 01033, Ukraine., Kreuchwig A; 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., Saupe J; 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., Fang L; 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., Diehl A; Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany., Schmieder P; Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany., Krause G; Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany., Rademann J; 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., Heinemann U; 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., Birchmeier W; Max Delbrück Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany., Oschkinat H; 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.
Jazyk:	angličtina
Zdroj:	Magnetic resonance (Gottingen, Germany) [Magn Reson (Gott)] 2021 Jun 02; Vol. 2 (1), pp. 355-374. Date of Electronic Publication: 2021 Jun 02 (Print Publication: 2021).
DOI:	10.5194/mr-2-355-2021
Abstrakt:	Dishevelled (Dvl) proteins are important regulators of the Wnt signalling pathway, interacting through their PDZ domains with the Wnt receptor Frizzled. Blocking the Dvl PDZ-Frizzled interaction represents a potential approach for cancer treatment, which stimulated the identification of small-molecule inhibitors, among them the anti-inflammatory drug Sulindac and Ky-02327. Aiming to develop tighter binding compounds without side effects, we investigated structure-activity relationships of sulfonamides. X-ray crystallography showed high complementarity of anthranilic acid derivatives in the GLGF loop cavity and space for ligand growth towards the PDZ surface. Our best binding compound inhibits Wnt signalling in a dose-dependent manner as demonstrated by TOP-GFP assays (IC 50 ∼ 50   µ M ) and Western blotting of β -catenin levels. Real-time PCR showed reduction in the expression of Wnt-specific genes. Our compound interacted with Dvl-1 PDZ (K D = 2.4   µ M ) stronger than Ky-02327 and may be developed into a lead compound interfering with the Wnt pathway. Competing Interests: The authors declare that they have no conflict of interest. (Copyright: © 2021 Nestor Kamdem et al.)
Databáze:	MEDLINE
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