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

  • ACS Med Chem Lett. 2016 May 10;7(7):676-80. doi: 10.1021/acsmedchemlett.6b00038.
Dai Cheng  1 ,  Jun Liu  1 ,  Dong Han  1 ,  Guobao Zhang  1 ,  Wenqi Gao  1 ,  Mindy H Hsieh  1 ,  Nicholas Ng  1 ,  Shailaja Kasibhatla  1 ,  Celin Tompkins  1 ,  Jie Li  1 ,  Auzon Steffy  1 ,  Fangxian Sun  1 ,  Chun Li  1 ,  H Martin Seidel  1 ,  Jennifer L Harris  1 ,  Shifeng Pan  1
Affiliations
  • 1. Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
PMID: 27437076 DOI: 10.1021/acsmedchemlett.6b00038
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.

Keywords
Porcupine inhibitor; Wnt signaling.
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