生物活性

• 靶点	β-catenin IC50:2.9nM

• 描述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]

• 动物研究
  剂量	Mice: 5 mg/kg[1] (p.o.), 100 mg/kg[3] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Nude mice[1] Dose 5 mg/kg Administration p.o. T1/2 ~1.18 h Tmax ~0.5 h

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02521844	Solid Tumors	Phase 1	Recruiting	August 2018	United States, Colorado ... more >> University of Colorado Anschutz Cancer Pavilion Recruiting Aurora, Colorado, United States, 80045 Principal Investigator: Wells A. Messersmith, MD, F.A.C.P.          United States, Texas MD Anderson Cancer Center Recruiting Houston, Texas, United States, 77030 Principal Investigator: Vivek Subbiah, MD          Singapore National University Hospital Recruiting Singapore, Singapore, 119228 Principal Investigator: David Tan Shao Peng          National Cancer Centre Singapore Recruiting Singapore, Singapore, 169610 Principal Investigator: Matthew Ng Chau Hsien          Spain Vall d'Hebron Institut d'Oncologia Not yet recruiting Barcelona, Spain Collapse <<

• 参考文献

• [1] Madan B, Ke Z, et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016 Apr 28;35(17):2197-207.

  [2] Madan B, McDonald MJ, et al. Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy. Bone Res. 2018 May 25;6:17.

  [3] Chee YC, Pahnke J, et al. Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche. Dev Cell. 2018 Sep 24;46(6):681-695.e5.

  [4] Madan B, Ke Z, Harmston N, Ho SY, Frois AO, Alam J, Jeyaraj DA, Pendharkar V, Ghosh K, Virshup IH, Manoharan V, Ong EH, Sangthongpitag K, Hill J, Petretto E, Keller TH, Lee MA, Matter A, Virshup DM. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016 Apr 28;35(17):2197-207. doi: 10.1038/onc.2015.280. Epub 2015 Aug 10. PMID: 26257057; PMCID: PMC4650263.

  [5] Madan B, McDonald MJ, Foxa GE, Diegel CR, Williams BO, Virshup DM. Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy. Bone Res. 2018 May 25;6:17. doi: 10.1038/s41413-018-0017-8. PMID: 29844946; PMCID: PMC5968037.

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