RXC004 (RXC-004, Zamaporvint) is a potent, selective Porcupine (PRCN) inhibitor, inhibits functional Wnt production from mouse L-Wnt3a cells with IC50 of 64 pM in luciferase reporters assays.
RXC004 had no effect on downstream Wnt signaling.
RXC004 inhibited palmitoylation of Wnt, RXC004 also inhibited Wnt5a secretion from L-Wnt5a cells and reduced levels of β-catenin in L-Wnt3a cells.
Porcupine inhibition by RXC004 downregulated mRNA expression of Wnt pathway targets Axin2, RNF43, c-Myc, CD44, and MMP7 in cell lines with RNF43 LoF mutations and RSPO3 fusions.
RXC004 inhibited proliferation of cell lines with RNF43 mutations and RSPO3 fusions in a concentration-dependent manner but had no effect on cell lines with mutations in downstream Wnt signaling.
RXC004 reduced the proportion of cells in S-phase, and strongly inhibited expression of the mitosis marker phospho-histone-H3 in cells with upstream aberrations in Wnt pathway components.
RXC004 treatment (5 mg/kg once daily) inhibited tumor growth in SNU-1411/NOD-SCID xenografts, with inhibition of c-Myc gene expression in tumor.