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

Cheng, Dai and Liu, Jun and Han, Dong and Zhang, Guobao and Hsieh, Hsin-I and Ng, Nicholas and Kasibhatla, Shailaja and Tompkins, Celin and Li, Jie and Steffy, Auzon and Seidel, Martin and Harris, Jennifer and Sun, Fangxian (2016) Discovery of a Novel Series of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors. ACS Med Chem Lett, 7 (7). pp. 676-680. ISSN 1948-5875

Abstract

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.

Item Type: Article
Date Deposited: 13 Oct 2016 00:45
Last Modified: 13 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/28227

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