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

Grätz L, Turku A, Kozielewicz P, Bowin CF, Scharf MM, Voss JH, Kinsolving J, Shekhani R, Oliva-Vilarnau N, Koolmeister T, Körber M, Lauschke VM, Löber S, Gmeiner P, Schulte G (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Journal of Biological Chemistry American Society for Biochemistry and Molecular Biology

Book Volume: 301

Article Number: 110751

Journal Issue: 11

DOI: 10.1016/j.jbc.2025.110751

Abstract

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 FZD6 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 with CRIS profile

Marlies Rippl Lehrstuhl für Organische Chemie II Stefan Löber Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

Karolinska Institute SE Sweden (SE)

How to cite

APA:

Grätz, L., Turku, A., Kozielewicz, P., Bowin, C.F., Scharf, M.M., Voss, J.H.,... Schulte, G. (2025). SAG1.3-derived Frizzled-targeting small-molecule compounds. Journal of Biological Chemistry, 301(11). https://doi.org/10.1016/j.jbc.2025.110751

MLA:

Grätz, Lukas, et al. "SAG1.3-derived Frizzled-targeting small-molecule compounds." Journal of Biological Chemistry 301.11 (2025).

BibTeX: Download