A Negative Allosteric Modulator of WNT Receptor Frizzled 4 Switches into an Allosteric Agonist

Gennaro Riccio, Sara Bottone, Giuseppe La Regina, Nadia Badolati, Sara Passacantilli, Giovanni Battista Rossi, Antonella Accardo, Monica Dentice, Romano Silvestri, Ettore Novellino, Mariano Stornaiuolo

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Abstract

The WNT pathway interconnects a network of signaling events involved in a huge plethora of cellular processes, from organogenesis to tissue homeostasis. Despite its importance, the exiguity of organic drugs directly targeting the members of the Frizzled family of WNT receptors has hampered progress across the whole spectrum of biological fields in which the signaling is involved. We here present FzM1.8, a small molecule acting as an allosteric agonist of Frizzled receptor FZD4. FzM1.8 derives from FzM1, a negative allosteric modulator of the receptor. Replacement of FzM1 thiophene with a carboxylic moiety induces a molecular switch in the lead and transforms the molecule into an activator of WNT signaling. We here show that, in the absence of any WNT ligand, FzM1.8 binds to FZD4, promotes recruitment of heterotrimeric G proteins, and biases WNT signaling toward a noncanonical route that involves PI3K. Finally, in colon cancer cells, we prove that the FZD4/PI3K axis elicited by FzM1.8 preserves stemness and promotes proliferation of undifferentiated cells.

Original languageEnglish
Pages (from-to)839-851
Number of pages13
JournalBiochemistry
Volume57
Issue number5
DOIs
Publication statusPublished - Feb 6 2018

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Riccio, G., Bottone, S., La Regina, G., Badolati, N., Passacantilli, S., Rossi, G. B., Accardo, A., Dentice, M., Silvestri, R., Novellino, E., & Stornaiuolo, M. (2018). A Negative Allosteric Modulator of WNT Receptor Frizzled 4 Switches into an Allosteric Agonist. Biochemistry, 57(5), 839-851. https://doi.org/10.1021/acs.biochem.7b01087