11 research outputs found
Thermogravimetric and evolved gas analyses of high ash Indian and Turkish coal pyrolysis and gasification
Discovery of a Novel Series of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors
Blockade of aberrant Wnt signaling is an attractive therapeutic approach in multiple cancers. We developed and performed a cellular high-throughput screen for inhibitors of Wnt secretion and pathway activation. Lead structure (GNF-1331) was identified from the screen. Further studies identified the molecular target of GNF-1331 as Porcupine, a membrane bound O-acyl transferase. Structure-activity relationship studies led to the discovery of a novel series of potent and selective Porcupine inhibitors. Compound 19, GNF-6231, demonstrated excellent pathway inhibition and induced robust anti-tumor efficacy in a mouse MMTV-WNT1 xenograft tumor model
Discovery of Pyridinyl Acetamide Derivatives as Potent Selective, and Orally Bioavailable Porcupine Inhibitors
[Image: see text] Blockade of aberrant Wnt signaling is an attractive therapeutic approach in multiple cancers. We developed and performed a cellular high-throughput screen for inhibitors of Wnt secretion and pathway activation. A lead structure (GNF-1331) was identified from the screen. Further studies identified the molecular target of GNF-1331 as Porcupine, a membrane bound O-acyl transferase. Structure–activity relationship studies led to the discovery of a novel series of potent and selective Porcupine inhibitors. Compound 19, GNF-6231, demonstrated excellent pathway inhibition and induced robust antitumor efficacy in a mouse MMTV-WNT1 xenograft tumor model
Kinetic studies of pyrolysis and combustion of Thar coal by thermogravimetry and chemometric data analysis
Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors
Blockade of aberrant Wnt signaling
is an attractive therapeutic
approach in multiple cancers. We developed and performed a cellular
high-throughput screen for inhibitors of Wnt secretion and pathway
activation. A lead structure (GNF-1331) was identified from the screen.
Further studies identified the molecular target of GNF-1331 as Porcupine,
a membrane bound O-acyl transferase. Structure–activity relationship
studies led to the discovery of a novel series of potent and selective
Porcupine inhibitors. Compound <b>19</b>, GNF-6231, demonstrated
excellent pathway inhibition and induced robust antitumor efficacy
in a mouse MMTV-WNT1 xenograft tumor model
Targeting Wnt-driven Cancer Through the inhibition of Porcupine by LGK974
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). 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. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN