2. Academic Validation
  3. Development of a triazole class of highly potent Porcn inhibitors

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.
Lin You 1,  Chengwei Zhang 1,  Nageswari Yarravarapu 2,  Lorraine Morlock 1,  Xiaolei Wang 1,  Lishu Zhang 2,  Noelle S Williams 1,  Lawrence Lum 2,  Chuo Chen 3
Affiliations

Affiliations

  • 1 Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3 Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: chuo.chen@utsouthwestern.edu.
PMID: 27876319 DOI: 10.1016/j.bmcl.2016.11.012
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.

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