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

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. 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.

SUBMITTER: Cheng D

PROVIDER: S-EPMC4948009 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Cheng Dai D Liu Jun J Han Dong D Zhang Guobao G Gao Wenqi W Hsieh Mindy H MH Ng Nicholas N Kasibhatla Shailaja S Tompkins Celin C Li Jie J Steffy Auzon A Sun Fangxian F Li Chun C Seidel H Martin HM Harris Jennifer L JL Pan Shifeng S

ACS medicinal chemistry letters 20160510 7

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 inhib ...[more]

PMID: 27437076

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