9rhg
FZD7 in complex with negative allosteric modulator C407
Structural highlights
FunctionFZD7_HUMAN Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Publication Abstract from PubMedTargeting the Frizzled family (FZD(1-10)) of WNT receptors pharmacologically has, despite substantial therapeutic potential, proven difficult. Given an almost complete lack of validated, effective small molecules targeting FZDs, no putative ligand binding site has so far been identified. In order to target FZD(7), a potential target for the treatment of intestinal tumors, we combine an approach of adapted docking setups and large molecular library docking screens, identifying compound C407. Applying pharmacological assays, genetically-encoded biosensors, site-directed mutagenesis, cryo-electron microscopy and molecular dynamics simulations, the compound binding site in the core of the seven transmembrane bundle is validated and C407 is confirmed as a negative allosteric modulator of WNT-induced and FZD-mediated WNT/beta-catenin signaling. In summary, we provide here the proof-of-principle that targeting FZDs with small molecule compounds is possible and effective. Future hit optimization and functional validation in disease-relevant in vitro and in vivo models will pave the way towards clinical exploration. In silico docking yields small molecule negative allosteric modulators targeting the core of Frizzled 7.,Scharf MM, Kinsolving J, Gratz L, Voss JH, Carrasco-Busturia D, Forsberg B, Kolb P, Schulte G Nat Commun. 2025 Dec 14;16(1):11138. doi: 10.1038/s41467-025-67147-z. PMID:41392205[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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