LGK974, CAS No. 1243244-14-5, is a highly potent, selective and orally bioavailable Porcupine inhibitor (Wnt signaling antagonist) with an IC50 ~0.4 nM. LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV–Wnt1 and a human head and neck squamouscell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. All LGK974-sensitive pancreatic cancer cell lines carried inactivating mutations of RNF43. Currently LGK974 is in the Phase I study to treat cancers that are driven by the Wnt pathway in a Wnt ligand-dependent manner.LGK974 is a highly potent, selective and orally bioavailable Porcupine inhibitor (Wnt signaling antagonist) with an IC50 ~0.4 nM. LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV–Wnt1 and a human head and neck squamouscell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. All LGK974-sensitive pancreatic cancer cell lines carried inactivating mutations of RNF43. Currently LGK974 is in the Phase I study to treat cancers that are driven by the Wnt pathway in a Wnt ligand-dependent manner.

Product information

CAS Number: 1243244-14-5

Molecular Weight: 396.44

Formula: C23H20N6O

Chemical Name: 2-(2',3-dimethyl-[2,4'-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide

Smiles: CC1=CC(=CC=N1)C1=NC=C(CC(=O)NC2=CC=C(C=N2)C2=CN=CC=N2)C=C1C

InChiKey: XXYGTCZJJLTAGH-UHFFFAOYSA-N

InChi: InChI=1S/C23H20N6O/c1-15-9-17(12-28-23(15)18-5-6-25-16(2)10-18)11-22(30)29-21-4-3-19(13-27-21)20-14-24-7-8-26-20/h3-10,12-14H,11H2,1-2H3,(H,27,29,30)

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO up to 100 mM

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

LGK974 was suggested to be used at 0.1 μM final concentration in vitro to completely block Wnt protein secretion.

In Vivo:

LGK974 was used to dose mice orally at 0.1-10 mg/kg once or twice per day to achieve good efficacy in xenograft models.

References:

1. Jiang X, et al. Proc Natl Acad Sci U S A. 2013, 110(31), 12649-12654.
2. Liu J, et al. Proc Natl Acad Sci U S A. 2013, 110(50), 20224-20229.

Products are for research use only. Not for human use.

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