**Background**
The Wnt signaling pathway plays a critical role in embryonic development, tissue homeostasis, and the maintenance of adult stem cells. Dysregulation of this pathway, particularly through the overactivation of Frizzled (FZD) receptors, is frequently implicated in the progression of various malignancies and the maintenance of cancer stem cells. Among these, Frizzled 7 (FZD7) has emerged as a significant therapeutic target due to its involvement in Wnt–β-catenin signaling and its expression in several cancer types. Selective inhibition of FZD7 offers a promising strategy to disrupt oncogenic signaling and impair stem cell function in both healthy and malignant tissues. In this context, we will introduce a potent FZD7 antagonist – Fz7-21.
**Definition**
Fz7-21 (Ac-LPSDDLEFWCHVMY-NH2) is a selective peptide antagonist that binds to the cysteine-rich domain (CRD) subclass of FZD7 receptors, with EC50 values of 58 nM for human FZD7 CRD and 34 nM for mouse FZD7 CRD.
**In Vitro Studies**
According to the Fz7-21 description, this peptide selectively binds to the FZD7 CRD, altering its conformation and the architecture of its lipid-binding groove. In terms of Fz7-21 biological activity, in vitro studies have demonstrated its ability to significantly impair Wnt signaling. Specifically, Fz7-21 (0-100 μM; 6 h) treated HEK293-TB cells showed an IC50 value of approximately 100 nM. Furthermore, Fz7-21 (1 μM) was found to block the WNT3A-mediated stabilization of β-catenin in mouse L cells with an IC50 value of approximately 50 nM. Beyond signaling inhibition, Fz7-21 (200 μM; 48 h) was shown to disrupt the function of LGR5+ stem cells in intestinal organoids. These results highlight the potential of Fz7-21 in cancer research, particularly where FZD7-driven stemness is a factor. In conclusion, Fz7-21 is a potent and selective peptide inhibitor of FZD7 that disrupts Wnt–β-catenin signaling and stem cell function.
Keywords
Fz7-21, 2247635-23-8, Ac-LPSDDLEFWCHVMY-NH2, Wnt, FZD7, conformation, lipid-binding groove, FZD7 CRD, Wnt-β-catenin, intestinal organoids, Inhibitor, inhibitor, inhibit
References
[1] Nile AH, et, al. A selective peptide inhibitor of Frizzled 7 receptors disrupts intestinal stem cells. Nat Chem Biol. 2018 Jun;14(6):582-590.
[2] Larasati Y, et, al. Unlocking the Wnt pathway: Therapeutic potential of selective targeting FZD7 in cancer. Drug Discov Today. 2022 Mar;27(3):777-792.