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 derivates 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 Axin2 and Lgr5 gene expression in human primary hepatocyte spheroids and reduced the viability of RNF43-mutated but not RNF43-wildtype pancreatic cancer cells. The small molecule acted as a paralog-nonselective negative allosteric modulator acting by limiting WNT- and WNT-surrogate induced receptor dynamics providing a valid proof-of-concept for targeting FZDs with small molecule compounds.