| Autor: |
Kinsolving, Julia, Grätz, Lukas, Voss, Jan Hendrik, Löw, Bente, Shorter, Emily, Jude, Baptiste, Lanner, Johanna T, Löber, Stefan, Gmeiner, Peter, Schulte, Gunnar |
| Zdroj: |
Journal of Medicinal Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
The Frizzled family (FZD1–10) of G protein-coupled receptors regulates WNT signaling mediating proliferative input. Dysregulation of FZD7and exaggerated WNT/β-catenin signaling is frequently observed in intestinal cancers. Therefore, it is attractive to develop therapeutics targeting FZD7for cancer treatment. Structure-based virtual screening has identified compound 28, which inhibited WNT/β-catenin signaling based on the luciferase-based reporter gene TOPFlash assay. However, upon pharmacological validation, compound 28 rather acts as a potent Firefly luciferase (Fluc) inhibitor (IC50= 30 nM), matching the reported IC50for compound 28-mediated inhibition in the TOPFlash assay. Moreover, we employed Fluc-independent assays, a FZD7-focused bioluminescence resonance energy transfer biosensor and quantitative PCR, to emphasize the inability of compound 28 to inhibit the WNT-3A-induced conformational dynamics in FZD7and transcription of Axin2,a WNT target gene. Thus, we underline the importance of counter screens to validate compounds that interfere with the detection technology used for compound screening. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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