生物活性

• 靶点	PORCN IC50:0.4nM

• 描述Wnt signaling is one of the essential pathways in oncogenesis that depends on the production of Wnt proteins. During the process of biosynthesis, Wnt undergoes palmitoylation (posttranslational acylation) mediated by PORCN, a membrane bound O-acyltransferase. LGK974 is a specific and potent PORCN inhibitor that inhibits Wnt signaling with an IC50 of 0.4 nM. In 293A cells transfected with human HA-tagged Wnt3A, the secretion of Wnt was strongly abrogated by LGK974 in a dose-dependent manner from 0.2 – 500 nM. The inhibitory activity of LGK974 was observed in all canonical Wnts tested, including Wnt1, 2, 3, 3A, 6, 7A, and 9A. Moreover, LGK974 effectively down-regulated the mRNA level of Wnt-dependent AXIN2 in human head and neck cancer cell line HN30 with an IC50 value of 0.3 nM. The HN30 colony numbers were also reduced by LGK974 at 1 and 10 μM. In the murine MMTV-driven Wnt1 model, oral administration of LGK974 at 0.3, 1.0, 3.0 mg/kg/d for 13 days led to significantly tumor growth delay compared with control groups. The inhibitory effect of 3 mg/kg LGK974 on both distal (AXIN2 mRNA) and proximal (phospho-LRP6) Wnt signaling events reached peak at 7 h after the last dose and diminished after 24 h. The administration of 3 mg/kg/d LGK974 induced tumor regression in a rat MMTV-Wnt1 xenograft tumor model. At the dose of 3 mg/kg/d for 14 days, LGK974 was well-tolerated without abnormal histopathological features showing in Wnt-dependent tissues. However, when rats received a very high dose of 20 mg/kg/d for 14 days, the loss of intestinal epithelium was observed. In the mouse xenograft model of HN30 cell line, the expression of AXIN2, a Wnt signaling target gene, was inhibited by a single dose of 3 mg/kg LGK974 to 5 – 40% between 5 and 10h post dose.
• 作用机制LGK interacts with PORCN to inhibit its acyltransferase activity.
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  293T	-	Function Assay	-	IC50 of 1 nM to compete off [3H]-GNF-1331 in a dose-dependent manner	24277854
  293T	-	Function Assay	-	IC50 of 0.4 nM to inhibits Wnt signaling in the aforementioned Wnt coculture assay	24277854
  Capan-2	1 μM	Growth Inhibition Assay	-	inhibits the growth of pancreatic cancer cell lines with RNF43 mutation	23847203

• 更多

• 动物研究
  剂量	Mice: 0.3 mg/kg - 3 mg/kg[1] (p.o.), 30 mg/kg[2] (p.o.)
  给药途径	p.o.

• 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
  NCT01351103	Pancreatic Cancer ... more >> BRAF Mutant Colorectal Cancer Melanoma Triple Negative Breast Cancer Head and Neck Squamous Cell Cancer Cervical Squamous Cell Cancer Esophageal Squamous Cell Cancer Lung Squamous Cell Cancer Collapse <<	Phase 1	Recruiting	August 20, 2020	United States, California ... more >> Novartis Investigative Site Recruiting Los Angeles, California, United States, 90024 United States, Maryland Novartis Investigative Site Recruiting Baltimore, Maryland, United States, 21287-0013 Contact: Ashley Elza O'Connor    +1 410 502 2377    aoconnor@jhmi.edu    Principal Investigator: Roisin Connolly          United States, Massachusetts Dana Farber Cancer Institute SC Withdrawn Boston, Massachusetts, United States, 02115 Dana Farber Cancer Institute SC-7 Recruiting Boston, Massachusetts, United States, 02215 Contact: Marios Giannakis, M.D., Ph.D.    617-632-6805    Marios_Giannakis@dfci.harvard.edu    Principal Investigator: Marios Giannakis, M.D., Ph.D.          United States, Michigan University of Michigan Comprehensive Cancer Center Onc Dept. Not yet recruiting Ann Arbor, Michigan, United States, 48109-0944 Contact: Cancer AnswerLine    800-865-1125       Principal Investigator: David Smith          Karmanos Cancer Institute Wayne St Recruiting Detroit, Michigan, United States, 48201 Contact: DeQuindalyn Moore    313-576-9371    moored@karmanos.org    Principal Investigator: Ulka A. Vaishampayan          United States, Texas University of Texas/MD Anderson Cancer Center MD Anderson 2 Recruiting Houston, Texas, United States, 77030-4009 Contact: Stepanek M. Vanda    713-792-2921    vstepane@mdanderson.org    Principal Investigator: Filip P. Janku          Netherlands Novartis Investigative Site Recruiting Rotterdam, Netherlands, 3075 EA Novartis Investigative Site Recruiting Utrecht, Netherlands, 3584CX Spain Novartis Investigative Site Recruiting Barcelona, Catalunya, Spain, 08035 Novartis Investigative Site Recruiting Barcelona, Catalunya, Spain, 08036 Novartis Investigative Site Recruiting Madrid, Spain, 28007 Novartis Investigative Site Recruiting Madrid, Spain, 28050 Collapse <<

• 参考文献

• [1] Liu J, Pan S, et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci U S A. 2013;110(50):20224-9