Development of a triazole class of highly potent Porcn inhibitors. Issue 24 (15th December 2016)

• Record Type: Journal Article
• Authors: You, Lin; Zhang, Chengwei; Yarravarapu, Nageswari; Morlock, Lorraine; Wang, Xiaolei; Zhang, Lishu; Williams, Noelle S.; Lum, Lawrence; Chen, Chuo
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 24(2016)
• Page Start: 5891
• Page End: 5895
• Publication Date: 2016-12-15
• Subjects: Porcupine -- Wnt signaling -- Triazole -- Triaryl -- Biaryl amide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.11.012
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.