Targeting frizzleds with small-molecule compounds-back to square one or light at the end of the tunnel?

The Frizzled (FZD) family of G protein-coupled receptors (GPCRs) are central mediators of Wingless/Int-1 (WNT) signaling that regulates embryonic development, stem cell function, and tissue homeostasis. This makes FZDs attractive therapeutic targets, for example, in cancer and fibrotic diseases. However, developing small-molecule drugs targeting these class F GPCRs has been extraordinarily difficult. Recent breakthrough achievements demonstrate that small-molecule allosteric modulators can successfully target the FZD core. Despite low potency, recent data show that the central cavity of FZDs is indeed druggable and that negative allosteric modulators (NAMs) can block agonist-induced oncogenic β-catenin signaling. Importantly, intrinsic FZD conformational rearrangements are required for FZD activation and signal initiation, supporting an integrated dynamic GPCR activation model for FZDs, which builds the functional and molecular basis for NAM action. Future optimization efforts will improve compound affinity, potency, and achieve FZD or cluster selectivity to minimize unwanted effects on active stem cell niches, for example in epithelia and bone while advancing toward clinical applications.