FzM1

FzM1 is a negative allosteric modulator (NAM) of Frizzled receptor FZD4. FzM1 reduces WNT5A-dependent WNT responsive element (WRE) activity (log EC_50inh= 6.2). FzM1 binds to an allosteric binding site located in intracellular loop 3 (ICL3) of FZD4 and alters the conformation of the receptor, ultimately inhibiting the WNT/β-catenin cascade^[1][2]. In Vitro:In HEK293 cells (co-transfected with FZD4 and a WNT reporter construct), FzM1 acts as a negative allosteric regulator of FZD4, inhibiting the WNT/β-catenin pathway without increasing the activity of the WNT reporter construct^[1]. In CaCo-2 cells, FzM1 (15 μM; 24 h, 48 h) resulted in decreased cell viability^[1]. In HEK293 cells expressing FZD4, FzM1 acts as a negative allosteric regulator of FZD4 signaling initiated by WNT5A, reducing WNT5A-dependent WRE activity^[1]. In Vivo:In the AGEs-RAGE activation model of Wistar rats, FPS-ZM1 (1 mg/kg/d; intraperitoneal injection; once a day; 4 weeks) reduced the production of Aβ1-40 and Aβ1-42 in the rat hippocampus, inhibited the increase of Aβ metabolism-related proteins (RAGE, BACE1 and APP), downregulated the expression of proinflammatory cytokines (p-NF-κB, TNF-α and IL-1β), upregulated the antioxidant defense system (reduced ROS and LPO levels, increased GSH content, SOD and GPx activity), and alleviated AGEs-induced memory impairment in rats^[1].