LGK-974

Catalog No.S7143 Synonyms: NVP-LGK974

LGK-974 Chemical Structure

Molecular Weight(MW): 396.44

LGK-974 is a potent and specific PORCN inhibitor, and inhibits Wnt signaling with IC50 of 0.4 nM in TM3 cells. Phase 1.

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2 Customer Reviews

  • AP1/Jun noncanonical Wnt activity measured in the presence of LGK974 (porcupine inhibitor) and JNK-IN-8 (JNK inhibitor) (both 1 μM). F: Aldosterone secretion during the same experiment (n=4). Results are expressed in mean SEM, and P values show significance between treatments and baseline control.

    J Clin Endocrinol Metab, 2015, 100(6): E836-44. LGK-974 purchased from Selleck.

    Nestin silencing inhibits the Wnt/β-catenin signaling in breast CSC. Nestin-si and Nestin-c breast CSC were cultured for 48 h, and the relative levels of target proteins and phosphorylation were determined by western blotting. Data are presented as the mean ± SD of the levels of target proteins vs. the β-actin control, or the phosphorylated vs. the total form, from six separate experiments. In addition, Nestinhigh in the presence or absence of LGK974 (1 nM), Nestinlow in the presence or absence of SB216763 (5 uM), and control CSC were tested for their proliferation via mammosphere formation assays. Quantitative analysis of the formed mammospheres. *P <0.05, vs. the Nestin-c or control, except for specifically indicated. CSC, cancer stem cell; SD, standard deviation.

    Breast Cancer Res 2014 16(4), 408. LGK-974 purchased from Selleck.

Purity & Quality Control

Choose Selective Wnt/beta-catenin Inhibitors

Biological Activity

Description LGK-974 is a potent and specific PORCN inhibitor, and inhibits Wnt signaling with IC50 of 0.4 nM in TM3 cells. Phase 1.
Features Orally bioavailable Porcupine-specific inhibitor that has been tested in Phase I clinical trials for treatment of malignancies dependent on Wnt ligands.
Targets
Porcn [1]
(TM3 cells)
In vitro

LGK974 effectively displaces [3H]-GNF-1331 with IC50 of 1 nM in the PORCN radioligand binding assay, and shows no major cytotoxicity in cells up to 20 µM. LGK974 shows comparable inhibitory activities against all tested Wnts with IC50 ranging from 0.05 to 2.4 nM, which is consistent with the genetic loss of PORCN phenotype. [1] LGK974 specifically inhibits the growth of three RNF43-mutant cell lines, HPAF-II, PaTu 8988S, and Capan-2. [2]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
293T  M123UGZ2dmO2aX;uJGF{e2G7 MU\JR|UxKG:oIEGgcm0hfG9iY3;tdIV1\SCxZn[gX|NJZS2JTl[tNVM{OSCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>? M1;L[lI1Ojd5OEW0
293T  NEDWeVlHfW6ldHnvckBCe3OjeR?= MmOyTWM2OMLib3[gNE41KG6PIITvJIlvcGmkaYTzJHdvfCC|aXfuZYxqdmdiaX6geIhmKGGob4LlcYVvfGmxbnXkJHdvfCClb3P1cJR2emViYYPzZZk> M132U|I1Ojd5OEW0
PaTu8988S MXfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MVWxJO69VcLi MkLUSG1UVw>? MXXpcohq[mm2czD0bIUh\3Kxd4ToJI9nKHCjbnPy[YF1cWNiY3HuZ4VzKGOnbHygcIlv\XNid3n0bOKhWk6INERCpI12fGG2aX;u M1\Q[|I{QDR5MkCz
HPAF-II NWn1e5JDT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHLQUHgyKM7:TdMg MkXqSG1UVw>? NWDmVZVmcW6qaXLpeJMhfGinIHfyc5d1cCCxZjDwZY5kemWjdHnjJINidmOncjDj[YxtKGyrbnXzJJdqfGkEoGLOSlQ{yqCvdYTheIlwdg>? Mn35NlM5PDd{MEO=
Capan-2 MVHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NGnzTVkyKM7:TdMg MWjEUXNQ NXu1TY4xcW6qaXLpeJMhfGinIHfyc5d1cCCxZjDwZY5kemWjdHnjJINidmOncjDj[YxtKGyrbnXzJJdqfGkEoGLOSlQ{yqCvdYTheIlwdg>? NHG4XWEzOzh2N{KwNy=>
PaTu 8988S  MXnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NYfGOIFpOSEQvF5CpC=> MVnEUXNQ M2XLTIlvcGmkaYTzJJRp\SCpcn;3eIghd2ZicHHuZ5Jm[XSrYzDjZY5k\XJiY3XscEBtcW6nczD3bZRpyqCUTl[0N412fGG2aX;uxsA> NXHiU3VoOjN6NEeyNFM>
HPAF-II  MnG4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4LLUVEh|ryPwrC= NGe0TFJFVVOR NYjxV5hmcW6qaXLpeJMhfGinIHfyc5d1cCCxZjDwZY5kemWjdHnjJINidmOncjDj[YxtKGyrbnXzJJdqfGkEoGLOSlQ{dXW2YYTpc47DqA>? MVuyN|g1PzJyMx?=

... Click to View More Cell Line Experimental Data

In vivo In a murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30), LGK974 (3 mg/kg) inhibits Wnt signaling in vivo and induces tumor regression without significant body weight loss in the mice. [1] LGK974 (5 mg/kg, p.o., BID) also inhibits tumor growth of RNF43-mutant pancreatic tumors (HPAF-II and Capan-2) in vivo. [2]

Protocol

Cell Research:

[2]

+ Expand
  • Cell lines: HPAF-II, PaTu 8988S, and Capan-2 cells
  • Concentrations: ~1 μM
  • Incubation Time: 3 days
  • Method:

    Cells are plated in growth medium in a 96-well plate at a density of 6,000–12,000 cells per well and treated with DMSO or 1 μM LGK974. After 3 d, the cells are treated with fresh growth medium containing 20 μM EdU, which is included in the Click-iT EdU Alexa Fluor 488 HCS assay kit, and the plate was incubated for 2 h at 37 °C in a humidified atmosphere containing 5% CO2. Cells are fixed with final 4% (mass/vol) paraformaldehyde for 30 min, washed with PBS, permeabilized, and stained with 50 μg/mL Hoechst in PBS for 30 min. After wash, the cells are proceeded to EdU detection according to the instruction of Click-iT EdU assay kit. Triplet wells are performed for each condition.


    (Only for Reference)
Animal Research:

[1]

+ Expand
  • Animal Models: A murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30)
  • Formulation: 10% (vol/vol) citrate buffer (pH 2.8)/90% (vol/vol) citrate buffer (pH 3.0) or 0.5% MC/0.5% Tween 80
  • Dosages: ~3 mg/kg daily
  • Administration: Oral gavage
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 79 mg/mL warmed (199.27 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents individually and in order:
2% DMSO+corn oil
5mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 396.44
Formula

C23H20N6O

CAS No. 1243244-14-5
Storage powder
Synonyms NVP-LGK974

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01351103 Suspended Pancreatic Adenocarcinoma|BRAF Mutant Colorectal Cancer|Other Tumor Types With Documented Genetic Alterations Upstream in the Wnt Signaling Pathway Novartis Pharmaceuticals|Novartis December 2011 Phase 1

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

Tel: +1-832-582-8158 Ext:3

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Frequently Asked Questions

  • Question 1:

    If LGK974 is a lipophilic or hydrophilic substance?

  • Answer:

    LGK974 is a lipophilic compound.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID