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Updated: Apr 11, 2026

Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
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Targeting frizzleds with small-molecule compounds-back to square one or light at the end of the tunnel?

Gunnar Schulte1

  • 1Section of Receptor Biology & Signaling, Department Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden.

The Journal of Biological Chemistry
|April 9, 2026
PubMed

Insights

Small molecules targeting Frizzled (FZD) receptors, key in Wingless/Int-1 (WNT) signaling, are challenging to develop. Recent findings show negative allosteric modulators can block oncogenic signaling by targeting the FZD core.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Frizzled (FZD) receptors are G protein-coupled receptors (GPCRs) crucial for Wingless/Int-1 (WNT) signaling.
  • WNT signaling regulates fundamental biological processes including embryonic development, stem cell function, and tissue homeostasis.
  • FZDs are attractive therapeutic targets for diseases like cancer and fibrosis, but developing drugs for them is difficult.

Purpose of the Study:

  • To investigate the druggability of the FZD receptor core for therapeutic intervention.
  • To explore the potential of small-molecule allosteric modulators, specifically negative allosteric modulators (NAMs), in targeting FZD receptors.
  • To understand the dynamic nature of FZD receptor activation and its implications for drug action.

Main Methods:

  • Utilized small-molecule allosteric modulators to target the FZD receptor core.
  • Investigated the ability of NAMs to block agonist-induced oncogenic β-catenin signaling.
  • Applied an integrated dynamic GPCR activation model to understand FZD function.

Main Results:

  • Demonstrated that the central cavity of FZD receptors is druggable, despite current low compound potency.
  • Showed that NAMs can effectively block oncogenic β-catenin signaling mediated by FZD activation.
  • Established that intrinsic FZD conformational rearrangements are essential for receptor activation and signal initiation.

Conclusions:

  • Small-molecule NAMs represent a viable strategy for targeting FZD receptors and inhibiting oncogenic WNT signaling.
  • Further optimization of compounds is needed to improve affinity, potency, and selectivity for clinical applications.
  • Understanding FZD dynamics provides a foundation for developing targeted therapies with minimized off-target effects on stem cell niches.
Keywords:
FZDFrizzledsG protein-coupled receptor (GPCR)WNT signalingclass F GPCRsdrug discoverymedicinal chemistrynegative allosteric modulators

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