Development of a triazole class of highly potent Porcn inhibitors

Lin You, Chengwei Zhang, Nageswari Yarravarapu, Lorraine Morlock, Xiaolei Wang, Lishu Zhang, Noelle S. Williams, Lawrence Lum, Chuo Chen

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The acyltransferase Porcupine (Porcn) is essential for the secretion of Wnt proteins which contribute to embryonic development, tissue regeneration, and tumorigenesis. We have previously discovered four molecular scaffolds harboring Porcn-inhibitory activity. Comparison of their structures led to the identification of a general scaffold that can be readily assembled by modular synthesis. We report herein the development of a triazole version of this new class of Porcn inhibitors. This study yielded IWP-O1, a Porcn inhibitor with an EC50 value of 80 pM in a cultured cell reporter assay of Wnt signaling. Additionally, IWP-O1 has significantly improved metabolic stability over our previously reported Porcn inhibitors.

Original languageEnglish (US)
Pages (from-to)5891-5895
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number24
DOIs
StatePublished - Dec 15 2016

Keywords

  • Biaryl amide
  • Porcupine
  • Triaryl
  • Triazole
  • Wnt signaling

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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