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

被引：45

作者：

Cheng, Dai ^{[1
]}

Liu, Jun ^{[1
]}

Han, Dong ^{[1
]}

Zhang, Guobao ^{[1
]}

Gao, Wenqi ^{[1
]}

Hsieh, Mindy H. ^{[1
]}

Ng, Nicholas ^{[1
]}

Kasibhatla, Shailaja ^{[1
]}

Tompkins, Celin ^{[1
]}

Li, Jie ^{[1
]}

Steffy, Auzon ^{[1
]}

Sun, Fangxian ^{[1
]}

Li, Chun ^{[1
]}

Seidel, H. Martin ^{[1
]}

Harris, Jennifer L. ^{[1
]}

Pan, Shifeng ^{[1
]}

机构：

[1] Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 07期

关键词：

Wnt signaling; Porcupine inhibitor; WNT SIGNALING PATHWAY; CANCER; DRIVEN; RNF43;

D O I：

10.1021/acsmedchemlett.6b00038

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

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.

引用

页码：676 / 680

页数：5

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