Preprints
https://doi.org/10.5194/mr-2021-20
https://doi.org/10.5194/mr-2021-20

  25 Feb 2021

25 Feb 2021

Review status: this preprint is currently under review for the journal MR.

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

Nestor Kamdem1,2, Yvette Roske3, Dmytro Kovalskyy4,6, Maxim O. Platonov4,6, Oleksii Balinskyi4,6, Annika Kreuchwig1,2, Jörn Saupe1,2, Liang Fang2,3, Anne Diehl1, Peter Schmieder1, Gerd Krause1, Jörg Rademann1,5, Udo Heinemann2,3, Walter Birchmeier3, and Hartmut Oschkinat1,2 Nestor Kamdem et al.
  • 1Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Robert-Rössle-Straße 10, 13125 Berlin, Germany
  • 2Institut für Chemie und Biochemie, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
  • 3Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
  • 4Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine
  • 5Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Straße 2 + 4, 14195 Berlin, Germany
  • 6Taras Shevchenko National University, 62 Volodymyrska, Kyiv 01033, Ukraine

Abstract. 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 (IC50 ~50 µM), 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 (Kd = 2.4 µM) stronger than Ky-02327 and may be developed into a lead compound interfering with the Wnt pathway.

Nestor Kamdem et al.

Status: final response (author comments only)

Comment types: AC – author | RC – referee | CC – community | EC – editor | CEC – chief editor | : Report abuse
  • CC1: 'Comment on mr-2021-20', Jie Zheng, 03 Mar 2021
    • AC1: 'Reply on CC1', Hartmut Oschkinat, 14 Apr 2021
    • AC3: 'Reply on CC1', Hartmut Oschkinat, 14 Apr 2021
  • RC1: 'Comment on mr-2021-20', Mingjie Zhang, 11 Mar 2021
    • AC2: 'Reply on RC1', Hartmut Oschkinat, 14 Apr 2021
  • RC2: 'Comment on mr-2021-20', Anonymous Referee #2, 15 Mar 2021
    • AC4: 'Reply on RC2', Hartmut Oschkinat, 14 Apr 2021

Nestor Kamdem et al.

Nestor Kamdem et al.

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