Z-3578 is an orally active small-molecule antagonist of MrgX2 with potent antipseudoallergic activity, exhibiting a K D value of 729 nM. Z-3578 effectively inhibits mast cell degranulation induced by substance P (SP) and C48/80, suppresses the release of β-hexosaminidase, significantly reduces the release of histamine and TNF-α, and decreases intracellular calcium flux. In a mouse pseudoallergy model, Z-3578 significantly alleviates paw swelling and dye extravasation, and reduces serum histamine levels. Z-3578 can be used for the study of pseudoallergic reactions [1].
In Vivo, Z-3578 (0.1-1 mg/mL, 1-10 mg/kg; i.g.; single dose) dose-dependently inhibits C48/80-induced pseudoallergic reactions in male C57BL/6 mice, with significant reductions in paw thickness, Evans blue extravasation, serum histamine release, and mast cell degranulation observed at doses of 0.5 mg/mL, 1 mg/mL, 5 mg/kg, and 10 mg/kg[1].
In Vitro, Z-3578 potently inhibits β-hexosaminidase release from human mast cell line LAD2 induced by SP and C48/80, with IC50 values of 4.90 μM and 6.18 μM[1]. Z-3578 (1-10 μM) concentration-dependently inhibits SP-induced histamine release from LAD2 human mast cells[1]. Z-3578 (1-10 μM; 6 h) concentration-dependently inhibits SP-induced TNF-α release from human mast cell line LAD2[1]. Z-3578 (10 μM; 30 min) inhibits intracellular calcium mobilization in MrgX2-His-tag-HEK293 cells and blocks MrgX2-mediated signaling pathways[1].
References:
[1]. Xia Z, et al. MrgX2-Targeting Ligand Screen for Antipseudoallergic Agents by Immobilized His-Tag-Fused Protein Technology. J Med Chem. 2025;68(5):5942-5953.
In Vivo, Z-3578 (0.1-1 mg/mL, 1-10 mg/kg; i.g.; single dose) dose-dependently inhibits C48/80-induced pseudoallergic reactions in male C57BL/6 mice, with significant reductions in paw thickness, Evans blue extravasation, serum histamine release, and mast cell degranulation observed at doses of 0.5 mg/mL, 1 mg/mL, 5 mg/kg, and 10 mg/kg[1].
In Vitro, Z-3578 potently inhibits β-hexosaminidase release from human mast cell line LAD2 induced by SP and C48/80, with IC50 values of 4.90 μM and 6.18 μM[1]. Z-3578 (1-10 μM) concentration-dependently inhibits SP-induced histamine release from LAD2 human mast cells[1]. Z-3578 (1-10 μM; 6 h) concentration-dependently inhibits SP-induced TNF-α release from human mast cell line LAD2[1]. Z-3578 (10 μM; 30 min) inhibits intracellular calcium mobilization in MrgX2-His-tag-HEK293 cells and blocks MrgX2-mediated signaling pathways[1].
References:
[1]. Xia Z, et al. MrgX2-Targeting Ligand Screen for Antipseudoallergic Agents by Immobilized His-Tag-Fused Protein Technology. J Med Chem. 2025;68(5):5942-5953.