A Putative Frizzled 7‑Targeting Compound Acts as a Firefly Luciferase Inhibitor
Kinsolving J, Grätz L, Voss JH, Löw B, Shorter E, Jude B, Lanner JT, Löber S, Gmeiner P, Schulte G (2024)
Publication Language: English
Publication Type: Journal article
Publication year: 2024
Journal
Book Volume: 67
Pages Range: 22332-22341
Journal Issue: 24
DOI: 10.1021/acs.jmedchem.4c02766
Abstract
The Frizzled family (FZD1-10) of G protein-coupled receptors regulates WNT signaling mediating proliferative input. Dysregulation of FZD7 and exaggerated WNT/β-catenin signaling is frequently observed in intestinal cancers. Therefore, it is attractive to develop therapeutics targeting FZD7 for 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 IC50 for 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 FZD7 and 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.
Authors with CRIS profile
Bente Löw
Lehrstuhl für Pharmazeutische Chemie
Stefan Löber
Lehrstuhl für Pharmazeutische Chemie
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Additional Organisation(s)
Involved external institutions
Sweden (SE)How to cite
APA:
Kinsolving, J., Grätz, L., Voss, J.H., Löw, B., Shorter, E., Jude, B.,... Schulte, G. (2024). A Putative Frizzled 7‑Targeting Compound Acts as a Firefly Luciferase Inhibitor. Journal of Medicinal Chemistry, 67(24), 22332-22341. https://doi.org/10.1021/acs.jmedchem.4c02766
MLA:
Kinsolving, Julia, et al. "A Putative Frizzled 7‑Targeting Compound Acts as a Firefly Luciferase Inhibitor." Journal of Medicinal Chemistry 67.24 (2024): 22332-22341.
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