SAG1.3-derived Frizzled-targeting small molecule compounds.

IF 4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Biological Chemistry Pub Date : 2025-09-22 DOI:10.1016/j.jbc.2025.110751

Lukas Grätz, Ainoleena Turku, Pawel Kozielewicz, Carl-Fredrik Bowin, Magdalena M Scharf, Jan H Voss, Julia Kinsolving, Rawan Shekhani, Nuria Oliva-Vilarnau, Tobias Koolmeister, Marlies Körber, Volker M Lauschke, Stefan Löber, Peter Gmeiner, Gunnar Schulte

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引用次数: 0

Abstract

Exaggerated Wingless/Int1 (WNT)/Frizzled (FZD) signaling contributes to pathologies including fibrosis and different forms of cancers. Thus, targeting FZDs as WNT receptors for therapeutic purposes constitutes a promising intervention if the imminent risk of unwanted side effects caused by the involvement of WNT/FZD signaling in stem cell regulation and tissue homeostasis can be controlled. Here, we derivatize SAG1.3, which acts through FZD₆ as a partial agonist. Screening of SAG1.3 derivatives identified compound 11 that competed with BODIPY-cyclopamine binding at different FZDs and inhibited WNT-induced FZD dynamics and β-catenin signaling in HEK293 cells. Furthermore, compound 11 blocked WNT-3A-induced Lgr5 gene expression in human primary hepatocyte spheroids and reduced the viability of RNF43-mutated but not RNF43-wildtype pancreatic cancer cells. Based on our data, we suggest that compound 11 acts on FZDs to limit WNT- and WNT-surrogate-induced receptor dynamics providing a valid proof-of-concept for targeting FZDs with small molecule compounds.

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sag1.3衍生的frizzed靶向小分子化合物。

过度的无翼/Int1 (WNT)/卷曲（FZD）信号有助于包括纤维化和不同形式的癌症在内的病理。因此，如果可以控制WNT/FZD信号参与干细胞调节和组织稳态所引起的不良副作用的风险，那么靶向FZDs作为WNT受体用于治疗是一种很有希望的干预措施。在这里，我们衍生了SAG1.3，它通过FZD6作为部分激动剂起作用。通过对SAG1.3衍生物的筛选，发现化合物11在不同的FZD位点与bodipy - cycloparamine结合，并抑制wnt诱导的HEK293细胞FZD动力学和β-catenin信号传导。此外，化合物11阻断了wnt - 3a诱导的人原代肝细胞球体中Lgr5基因的表达，降低了rnf43突变而非rnf43野生型胰腺癌细胞的活力。根据我们的数据，我们认为化合物11作用于FZDs以限制WNT-和WNT-替代物诱导的受体动力学，这为用小分子化合物靶向FZDs提供了有效的概念证明。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Biological Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry

自引率

4.20%

发文量

1233

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