Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors

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• 作者：Dai Cheng ; Jun Liu ; Dong Han ; Guobao Zhang ; Wenqi Gao ; Mindy H. Hsieh ; Nicholas Ng ; Shailaja Kasibhatla ; Celin Tompkins ; Jie Li ; Auzon Steffy ; Fangxian Sun ; Chun Li ; H. Martin Seidel ; Jennifer L. Harris ; Shifeng Pan
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：7
• 期：7
• 页码：676-680
• 全文大小：290K
• 年卷期：0
• ISSN：1948-5875

文摘

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.