Targeting YAP-TEAD Interaction with Honokiol to Inhibit Melanoma Progression and Metastasis.

The Hippo-YAP/TEAD pathway plays a central role in melanoma progression by regulating tumor cell proliferation, survival, and migration. Using a NanoLuc Binary Technology (NanoBiT) protein-protein interaction assay, we screened honokiol-based small molecules and identified several analogues that disrupt the YAP-TEAD interaction. HK03 was the most effective analogue, leading to a pronounced reduction in Cyr61 levels and diminished Erk and Akt phosphorylation in B16-F10 melanoma cells. HK03 also blocked epithelial-mesenchymal transition (EMT) and impaired melanoma cell migration in wound-healing assays. In vivo, HK03 treatment markedly reduced metastatic burden in a B16-F10 lung metastasis model. These findings suggest that honokiol derivatives, particularly HK03, represent potential lead compounds for targeting the YAP-TEAD axis in melanoma therapy.