ETC-159 (ETC-1922159) is an orally available, potent porcupine inhibitor with an IC50 of 2.9 nM for inhibiting β-catenin reporter activity in STF3A cells.
Storage Temp
Store at -20°C
Shipped In
Ice chest + Ice pads
Grade
Moligand™
Action Type
INHIBITOR
Mechanism of action
Inhibitor of porcupine O-acyltransferase
Product Description
Information
ETC-159 ETC-159 (ETC-1922159) is an orally available, potent porcupine inhibitor with an IC50 of 2.9 nM for inhibiting β-catenin reporter activity in STF3A cells.
Targets
Porcn
In vitro
ETC-159 treatment causes decreased abundance of Wnt3a-stabilized β-catenin protein in both mouse L cells and HEK293 cells. ETC-159 inhibits β-catenin signaling in response to multiple active Wnts. ETC-159 inhibits mouse PORCN with an IC50 of 18.1\u2009nM, whereas the IC50 for Xenopus Porcn is approximately fourfold higher (70\u2009nM).
In vivo
ETC-159 is orally bioavailable and effectively inhibits the growth of mouse mammary tumor virus-Wnt1 tumors. After a single oral dose of 5\u2009mg/kg in mice, ETC-159 is rapidly absorbed into the blood with a Tmax of ~0.5\u2009h and oral bioavailability of 100%. The plasma half-life is ~1.18\u2009h and its concentration in the blood remained above the in vitro IC50 for at least 16\u2009h. Treatment of mice with increasing doses of ETC-159 leads to a dose-related increase in exposure. ETC-159 also effectively inhibits Wnt autocrine signaling and growth of teratocarcinomas. ETC-159 effectively inhibits the growth and induces differentiation of colon cancers with RSPO translocations and induces global remodeling of gene expression. Suppression of Wnt/β-catenin signaling with ETC-159 in genetically defined tumors induces irreversible cellular differentiation thus preventing regrowth of these tumors.
1.Ho SY, Keller TH. (2015) The use of porcupine inhibitors to target Wnt-driven cancers.. Bioorg Med Chem Lett, 25 (23):(5472-6). [PMID:26522946]
2.Madan B, Ke Z, Harmston N, Ho SY, Frois AO, Alam J, Jeyaraj DA, Pendharkar V, Ghosh K, Virshup IH et al.. (2016) Wnt addiction of genetically defined cancers reversed by PORCN inhibition.. Oncogene, 35 (17):(2197-207). [PMID:26257057]
3.Ho SY, Alam J, Jeyaraj DA, Wang W, Lin GR, Ang SH, Tan ESW, Lee MA, Ke Z, Madan B et al.. (2017) Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors.. J Med Chem, 60 (15):(6678-6692). [PMID:28671458]
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