Development of a triazole class of highly potent Porcn inhibitors

Bioorg Med Chem Lett. 2016 Dec 15;26(24):5891-5895. doi: 10.1016/j.bmcl.2016.11.012. Epub 2016 Nov 11.

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 80pM in a cultured cell reporter assay of Wnt signaling. Additionally, IWP-O1 has significantly improved metabolic stability over our previously reported Porcn inhibitors.

Keywords: Biaryl amide; Porcupine; Triaryl; Triazole; Wnt signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases
  • Dose-Response Relationship, Drug
  • Humans
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / metabolism
  • Molecular Structure
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • Membrane Proteins
  • Triazoles
  • Acyltransferases
  • PORCN protein, human