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

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.