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.

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

Figure 1

Representative structures of the four classes of IWPs (1–4) identified from HTS.

Figure 2

The general structure of IWP (5) and the effects of the biaryl and phenyl groups (6–8).

Figure 3

The molecular scaffold (9) of interest in this study and the synthetic route for this triazole class of IWP molecules.

Figure 4

Biochemical characterization of IWP-O1 (17). HeLa cells which exhibit high levels of cell autonomous Wnt signaling, were incubated for 24 h with DMSO, 17, or LGK974. Cell lysates were then subjected to Western blot analysis for biochemical markers of Wnt signaling (LRP6 and Dvl2/3 phosphorylation).