LGK974 - CAS 1243244-14-5
Catalog number:
1243244-14-5
Category:
Inhibitor
Not Intended for Therapeutic Use. For research use only.
COA:
Inquire
Targets:
Porcupine
Description:
LGK974 is a selective and orally bioavailable Porcupine inhibitor under development for the treatment of cancers that are driven by the Wnt pathway in a Wnt ligand-dependent manner. A Phase I study of LGK974 in patients with melanoma or lobular breast cancer is currently ongoing.
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Appearance:
white solid powder
Synonyms:
LGK-974; LGK974; LGK 974.
MSDS:
Inquire
Current Developer:
Novartis.
1.Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.
Liu J1, Pan S, Hsieh MH, Ng N, Sun F, Wang T, Kasibhatla S, Schuller AG, Li AG, Cheng D, Li J, Tompkins C, Pferdekamper A, Steffy A, Cheng J, Kowal C, Phung V, Guo G, Wang Y, Graham MP, Flynn S, Brenner JC, Li C, Villarroel MC, Schultz PG, Wu X, McNamara Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20224-9. doi: 10.1073/pnas.1314239110. Epub 2013 Nov 25.
Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that 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 squamous cell carcinoma model (HN30).
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