Zamaporvint (RXC004) is a selective, orally active and potent inhibitor of the Wnt pathway that acts on the membrane-bound fatty acyltransferase porcupine to block Wnt ligand palmitoylation, secretion, and pathway activation.Zamaporvint has shown anti-tumor and anti-proliferative activity in a wide range of cancer cell lines.

L-wnt3a cells:64 pM

Treatment of L-wnt3a cells with Zamaporvint (300 nM, 48 h) dose-dependently reduced the ability to activate β-catenin responsive luciferase reporter gene in conditioned medium, with an IC50 of 64 pM. The addition of recombinant Wnt3a restored luciferase activity, indicating no impact on downstream Wnt signaling transduction[1].The impact of Zamaporvint (100 nM, 24 h) on proliferation reflected a concentration-dependent downregulation of c-Myc mRNA. There was a decrease in the proportion of cells in the S phase, and a strong inhibition of the expression of mitotic marker phosphorylated histone-H3 in cells with aberrant upstream Wnt pathway components, suggesting cell cycle arrest. Additionally, an additive effect was observed at the same dose, revealing a reduction in its immunosuppressive properties after administration[1].

Zamaporvint, administered orally at doses of 1.5 mg/kg or 5 mg/kg twice daily, or 5 mg/kg once daily for 28 days, has demonstrated the ability to reduce tumor growth. In ligand-dependent SNU-1411, AsPC1, and HPAF II models with observable inhibition of Wnt-responsive gene expression (including cMyc), as well as in Wnt ligand-independent HCT116 xenograft models, tumor growth remained unaffected[1].At a dose of 1.5 mg/kg and 5 mg/kg once daily, Zamaporvint reduced the number of Ki67-positive cells in the overall tumor area, with a more pronounced effect in the differentiated tumor regions. Its anti-tumor effects were observed in the B16F10 "cold" tumor model through the inhibition of immune evasion[1].Zamaporvint, at doses of 1.5 or 5 mg/kg once daily, stimulated the host tumor immune response by decreasing bone marrow-derived suppressor cells within B16F10 tumors. It also exhibited a synergistic effect with anti-programmed cell death protein-1 (PD-1) to increase the proportion of regulatory T cells (CD8+/CT26) within the tumor[1].