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

Q3 Physics and Astronomy

Magnetic resonance (Gottingen, Germany) Pub Date : 2021-02-25 DOI:10.2210/pdb6zc7/pdb

N. Kamdem, Y. Roske, D. Kovalskyy, M. Platonov, O. Balinskyi, A. Kreuchwig, J. Saupe, L. Fang, A. Diehl, P. Schmieder, G. Krause, J. Rademann, U. Heinemann, W. Birchmeier, H. Oschkinat

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引用次数: 3

Abstract

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.

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散乱蛋白的PDZ结构域的小分子抑制剂可中断Wnt信号传导

摘要disheveled (Dvl)蛋白是Wnt信号通路的重要调节因子，通过其PDZ结构域与Wnt受体卷曲相互作用。阻断Dvl PDZ/ frizzed相互作用代表了一种潜在的癌症治疗方法，这刺激了小分子抑制剂的鉴定，其中包括抗炎药Sulindac和key -02327。为了开发结合更紧密、无副作用的化合物，我们研究了磺胺类化合物的构效关系。x射线晶体学显示，GLGF环腔中邻氨基苯酸衍生物具有高度互补性，配体向PDZ表面生长。通过TOP-GFP检测(IC50 ~50µM)和Western blotting检测β-catenin水平，我们的最佳结合化合物以剂量依赖的方式抑制Wnt信号传导。实时荧光定量PCR显示wnt特异性基因表达减少。该化合物与Dvl-1 PDZ (Kd = 2.4µM)的相互作用强于key -02327，可能成为干扰Wnt通路的先导化合物。

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