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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
J. Biol. Chem. - (-) 110751 [2025-09-22; online 2025-09-22]
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.
Chemical Biology Consortium Sweden (CBCS) [Collaborative]
PubMed 40992662
DOI 10.1016/j.jbc.2025.110751
Crossref 10.1016/j.jbc.2025.110751
pii: S0021-9258(25)02603-1