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 language | English |
|---|---|
| Pages (from-to) | 839-851 |
| Number of pages | 13 |
| Journal | Biochemistry |
| Volume | 57 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - Feb 6 2018 |
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ASJC Scopus subject areas
- Biochemistry
Cite this
A Negative Allosteric Modulator of WNT Receptor Frizzled 4 Switches into an Allosteric Agonist. / Riccio, Gennaro; Bottone, Sara; La Regina, Giuseppe; Badolati, Nadia; Passacantilli, Sara; Rossi, Giovanni Battista; Accardo, Antonella; Dentice, Monica; Silvestri, Romano; Novellino, Ettore; Stornaiuolo, Mariano.
In: Biochemistry, Vol. 57, No. 5, 06.02.2018, p. 839-851.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A Negative Allosteric Modulator of WNT Receptor Frizzled 4 Switches into an Allosteric Agonist
AU - Riccio, Gennaro
AU - Bottone, Sara
AU - La Regina, Giuseppe
AU - Badolati, Nadia
AU - Passacantilli, Sara
AU - Rossi, Giovanni Battista
AU - Accardo, Antonella
AU - Dentice, Monica
AU - Silvestri, Romano
AU - Novellino, Ettore
AU - Stornaiuolo, Mariano
PY - 2018/2/6
Y1 - 2018/2/6
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.biochem.7b01087
DO - 10.1021/acs.biochem.7b01087
M3 - Article
VL - 57
SP - 839
EP - 851
JO - Biochemistry
JF - Biochemistry
SN - 0006-2960
IS - 5
ER -