product name LGK974 (WNT974)
Description: LGK-974, also known as WNT974 and NVP-LGK974, is a potent, orally bioavailable and specific PORCN inhibitor, and inhibits Wnt signaling with IC50 of 0.4 nM in TM3 cells. LGK974 binds to and inhibits PORCN in the endoplasmic reticulum (ER), which blocks post-translational acylation of Wnt ligands and inhibits their secretion. This prevents the activation of Wnt ligands, interferes with Wnt-mediated signaling, and inhibits cell growth in Wnt-driven tumors.
References: Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9; Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12649-54.
396.44
Formula
C23H20N6O
CAS No.
1243244-14-5
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 79 mg/mL (199.3 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
2% DMSO+corn oil: 5 mg/mL
Synonyms
NVP-LGK974
other peoduct :
| In Vitro |
In vitro activity: 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. LGK974 specifically inhibits the growth of three RNF43-mutant cell lines, HPAF-II, PaTu 8988S, and Capan-2. Kinase Assay: Cell Assay: 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. |
|---|---|
| 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. LGK974 (5 mg/kg, p.o., BID) also inhibits tumor growth of RNF43-mutant pancreatic tumors (HPAF-II and Capan-2) in vivo. |
| Animal model | A murine MMTV-Wnt1 tumor model and a human head and neck squamous cell carcinoma model (HN30) |
| Formulation & Dosage | Dissolved in 010% (vol/vol) citrate buffer (pH 2.8)/90% (vol/vol) citrate buffer (pH 3.0) or 0.5% MC/0.5% Tween 80; 3 mg/kg; Oral gavage |
| References | Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9; Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12649-54. |
