title: 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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Dai
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Guobao
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Gao
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Mindy H
authors.initials: MH
authors.lastname: Hsieh
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ng
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Celin
authors.initials: C
authors.lastname: Tompkins
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Auzon
authors.initials: A
authors.lastname: Steffy
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Fangxian
authors.initials: F
authors.lastname: Sun
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
authors.affiliation: Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Pan
keywords: Porcupine inhibitor; Wnt signaling