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SAG1.3-derived Frizzled-targeting small-molecule compounds
Lukas Grätz1, Ainoleena Turku1, Pawel Kozielewicz1
1Karolinska Institutet, Department Physiology & Pharmacology, Sec. Receptor Biology & Signaling, Biomedicum, Stockholm, Sweden.
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.
Insights
Researchers developed compound 11 to target Frizzled (FZD) receptors, inhibiting Wingless/Int1 (WNT) signaling implicated in cancer and fibrosis. This small molecule shows promise for therapeutic intervention by controlling WNT-FZD pathway dynamics.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Aberrant Wingless/Int1 (WNT) signaling through Frizzled (FZD) receptors drives pathologies like fibrosis and cancer.
- Targeting FZD receptors offers therapeutic potential but requires managing risks associated with WNT-FZD pathway roles in tissue homeostasis and stem cell regulation.
Purpose of the Study:
- To derivatize SAG1.3, a SMO agonist acting via FZD6, to develop novel small-molecule inhibitors of WNT-FZD signaling.
- To investigate the therapeutic potential of these derivatives, specifically compound 11, in preclinical models.
Main Methods:
- Derivatization of SAG1.3 and screening for compounds that interact with FZD receptors.
- Assessing compound 11's ability to inhibit WNT-induced FZD dynamics and beta-catenin signaling in HEK293 cells.
- Evaluating compound 11's effect on LGR5 gene expression in primary hepatocyte spheroids and its impact on pancreatic cancer cell viability.
Main Results:
- Compound 11 competed with BODIPY-cyclopamine binding across various FZDs, inhibiting WNT-induced FZD dynamics and beta-catenin signaling.
- Compound 11 blocked WNT-3A-induced LGR5 expression in hepatocyte spheroids.
- Compound 11 selectively reduced the viability of RNF43-mutated pancreatic cancer cells.
Conclusions:
- Compound 11 effectively targets FZD receptors, limiting WNT and WNT-surrogate-induced receptor dynamics.
- This study provides proof of concept for utilizing small molecules to target FZD receptors therapeutically.
- Compound 11 demonstrates potential for treating cancers with specific mutations, like RNF43-mutated pancreatic cancer.
