Porcupine inhibitors LGK-974 and ETC-159 inhibit Wnt/β-catenin signaling and result in inhibition of the fibrosis

Objectives

We evaluated potential therapeutic efficacy of LGK-974 and ETC-159 in fibrotic scleroderma cells.

Methods

Primary scleroderma dermal fibroblast cells of mouse origin (SSc fibroblasts) and primary fibrotic lung fibroblast cells of human origin (CCL-191) were used in this study. PORCN inhibitors LGK-974 (S7143, 1 μM; Selleckchem, USA) and ETC-159 (S7143, 10 μM; Selleckchem, USA) were used. The possible therapeutic effects of LGK-974 and ETC-159 on scleroderma cells and fibrosis cells were examined. Cell viability experiments were performed for each substance, and the expression levels of WNT and fibrosis marker genes were determined by qPCR. Western blotting was also used to determine collagen, fibronectin and α-SMA protein markers.

Results

This study showed that LGK-974 and ETC-159 probable protein-cysteine N-palmitoyltransferase porcupine (PORCN) inhibitors exert potent antifibrotic effects and reduce fibrosis by modulating the TGF-β signaling pathway in scleroderma cells. Using LGK-974 and ETC-159 PORCN inhibitors, either alone or in combination, can affect collagen deposition and fibrosis in patients with SSc.

Conclusions

LGK-974 and ETC-159 may be a possible long-term therapeutic target for scleroderma.