ETC-159 is a novel potent PORCN inhibitor with IC50 value of 2.9nM for inhibition of β-catenin reporter activity. It blocks the secretion and activity of all Wnts. It effectively inhibited the secretion of WNT3A into culture media at 100nM, but did not inhibit β-catenin signaling in STF cells supplemented with Wnt3A-conditioned medium. ETC-159 at 100nM treatment also caused decreased abundance of Wnt3a-stabilizedβ-catenin protein in both mouse L cells and HEK293 cells post 6-24h. ETC-159 inhibited the growth of mouse mammary tumor virus (MMTV)-Wnt1 tumors orally administrated with ETC-159 at 1, 3 and 10mg/kg. Similar effect of tumor growth inhibition by ETC-159 could be observed on athymic nude mice bearing PA-1 or NCCIT xenografts. Also it was remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. Inhibition of PORCN by ETC-159 in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers[4]. Bones of mice treated with ETC-159 at doses of 3, 10 and 30mg/kg had loss-of-bone volume and density within 4 weeks of exposure[5].
作用机制
ETC-159 potently inhibited PORCN, palmitoleation activity of which is essential for Wnts for their secretion and binding to the Frizzled receptors.[4]
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