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Development of a triazole class of highly potent Porcn inhibitors.

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.

SUBMITTER: You L

PROVIDER: S-EPMC5142825 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Development of a triazole class of highly potent Porcn inhibitors.

You Lin L Zhang Chengwei C Yarravarapu Nageswari N Morlock Lorraine L Wang Xiaolei X Zhang Lishu L Williams Noelle S NS Lum Lawrence L Chen Chuo C

Bioorganic & medicinal chemistry letters 20161111 24

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 yiel ...[more]

PMID: 27876319

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