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]
ETC-159 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HPAF-II cells
100 nM
72 h
Wnt inhibition increased cell surface EGFR levels
J Clin Invest. 2024 Jan 23;134(6):e171222.
AsPC-1 cells
100 nM
72 h
Wnt inhibition increased cell surface EGFR levels
J Clin Invest. 2024 Jan 23;134(6):e171222.
143B
100 nM
72 h
To evaluate the effect of ETC-159 on angiogenesis in osteosarcoma cells, showing significant reduction in vessel length and surface area
Int J Mol Sci. 2023 Mar 1;24(5):4759.
SJSA-1
100 nM
72 h
To evaluate the effect of ETC-159 on angiogenesis in osteosarcoma cells, showing significant reduction in vessel length and surface area
Int J Mol Sci. 2023 Mar 1;24(5):4759.
HPAF-II cells
100 nM
approximately 2 weeks
ETC-159 significantly inhibited the growth of HPAF-II cells in 2D culture.
J Clin Invest. 2022 Jun 15;132(12):e156305.
PaTu8988T cells
1 µM
48 h
To evaluate the effect of ETC-159 on HR and FA pathway gene expression, results showed significant reduction in BRCA1, BRCA2, FANCD2, and RAD51 expression.
EMBO Mol Med. 2021 Apr 9;13(4):e13349.
AsPC-1 cells
100 nM
48 h
To evaluate the effect of ETC-159 on homologous recombination repair, results showed ~40% reduction in GFP-positive cells.
EMBO Mol Med. 2021 Apr 9;13(4):e13349.
HPAF-II cells
100 nM
48 h
To evaluate the effect of ETC-159 on HR and FA pathway gene expression, results showed significant reduction in BRCA1, BRCA2, FANCD2, and RAD51 expression.
EMBO Mol Med. 2021 Apr 9;13(4):e13349.
PA-1 teratocarcinoma cells
35 nM
24 h
Inhibition of endogenous Wnt/β-catenin signaling and soft agar colony formation
Oncogene. 2016 Apr 28;35(17):2197-207.
HeLa cells
100 nM
16 h
Inhibition of Wnt3A palmitoleation, demonstrating that ETC-159 and ETC-131 block Wnt secretion by preventing the interaction of Wnt with Wntless
Oncogene. 2016 Apr 28;35(17):2197-207.
HEK293 cells
2.9 nM
24 h
Inhibition of Wnt/β-catenin reporter activity, confirming ETC-159 and ETC-131 as potent and specific inhibitors of Wnt secretion
To evaluate the tumor growth inhibition effect of ETC-159 and GDC-0941 combination therapy. The combination treatment significantly suppressed tumor growth, outperforming monotherapy.
Oncogene. 2019 Oct;38(40):6662-6677
Mice
C57/BL6 mice
Oral
3–30 mg/kg
Daily or every other day for 4-8 weeks
To evaluate the skeletal effects of PORCN inhibitor ETC-159, which resulted in reduced bone volume and density, along with increased bone marrow adipocytes. Concurrent use of alendronate mitigated bone loss.
Bone Res. 2018 May 25;6:17
BALB/c nude mice
Osteosarcoma xenograft model
Oral gavage
30 mg/kg
Once daily for 15 days
To evaluate the therapeutic effect of ETC-159 on osteosarcoma xenograft models, showing increased tumor necrosis and reduced angiogenesis
Int J Mol Sci. 2023 Mar 1;24(5):4759.
NSG mice
Patu8988T and Patu8988S xenograft models
Oral gavage
15 mg/kg
Once every day (q.d.) for several weeks
ETC-159 failed to suppress Patu8988T orthotopic tumor growth but significantly inhibited Patu8988S tumor growth.
J Clin Invest. 2022 Jun 15;132(12):e156305.
NSG mice
HPAF-II xenograft model
Oral gavage
37.5 mg/kg
Daily administration for 56 hours
To evaluate the effect of ETC-159 on HR and FA pathway gene expression, results showed significant reduction in BRCA1, BRCA2, FANCD2, and RAD51 expression.
EMBO Mol Med. 2021 Apr 9;13(4):e13349.
BALB/c nude mice
MMTV-Wnt1 tumor model
Oral gavage
1, 3, 10 mg/kg
Once daily for 7 days
ETC-159 significantly inhibited tumor growth, promoted relocalization of β-catenin from nucleus and cytoplasm to the membrane, and downregulated Wnt target gene expression
Oncogene. 2016 Apr 28;35(17):2197-207.
Mouse
BP transgenic melanoma model
Oral
200 μg
Every 3 days
In the autochthonous melanoma model, the ETC-159 PORCN inhibitor stabilized primary tumor progression, increased tumor-infiltrating CD8+ T cells, and reduced the number of tumor-resident Tregs
Cell Rep. 2021 May 4;35(5):109071.
Mice
HPAF-II orthotopic xenograft model
Oral
30 mg/kg
Once daily for 28 days
ETC-159 significantly inhibited the growth of HPAF-II orthotopic xenografts and led to pronounced histomorphological changes.
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