2. Academic Validation
  3. Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors

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

Affiliation

  • 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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