SAG1.3-derived Frizzled-targeting small-molecule compounds
Exaggerated Wingless/Int1 (WNT)-Frizzled (FZD) signaling contributes to pathologies, including fibrosis and different forms of cancer. 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 (SMO agonist), which acts through FZD<sub>6</sub> as a partial agonist. Screening of SAG1.3 derivatives identified compound 11 that competed with BODIPY (boron-dipyrromethene)-cyclopamine binding at different FZDs and inhibited WNT-induced FZD dynamics and β-catenin signaling in human embryonic kidney 293 (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.
Authors
- Carl-Fredrik Bowin (ORCID: https://orcid.org/0000-0001-9090-9493)
- Nuria Oliva‐Vilarnau (ORCID: https://orcid.org/0000-0002-3083-6701)
- Jan Voss (ORCID: https://orcid.org/0000-0003-0595-4607)
- Paweł Kozielewicz (ORCID: https://orcid.org/0000-0003-1414-3566)
- Tobias Koolmeister
- Volker Martin Lauschke (ORCID: https://orcid.org/0000-0002-1140-6204)
- Julia Kinsolving (ORCID: https://orcid.org/0000-0002-0431-8222)
- Gunnar Schulte (ORCID: https://orcid.org/0000-0002-2700-7013)
- Lukas Grätz (ORCID: https://orcid.org/0000-0001-6755-0742)
- Magdalena M. Scharf (ORCID: https://orcid.org/0000-0002-3305-3956)
- Ainoleena Turku (ORCID: https://orcid.org/0000-0003-0959-7221)
- Peter Gmeiner (ORCID: https://orcid.org/0000-0002-4127-197X)
- Rawan Shekhani (ORCID: https://orcid.org/0000-0002-4632-2131)
- Stefan Löber
- Marlies Körber
Institutions
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE)
Publication Details
- Journal
- Journal of Biological Chemistry
- Published
- 2025-09-22
- DOI
- https://doi.org/10.1016/j.jbc.2025.110751
- Citations
- 1
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- McGill University
- Diamond Light Source
- European Federation of Pharmaceutical Industries and Associations
- Wenner-Gren Stiftelserna
- European Commission
- Deutsche Forschungsgemeinschaft
- Cancerfonden
- Svenska Sällskapet för Medicinsk Forskning
- Karolinska Institutet
- Novo Nordisk
- Kungliga Tekniska Högskolan
- Vetenskapsrådet
- Stiftelsen Lars Hiertas Minne