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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The Hippo-YAP/TEAD pathway is crucial for melanoma progression, controlling cell proliferation, survival, and migration.
• Targeting this pathway presents a potential therapeutic strategy for melanoma.

Purpose of the Study:

• To screen honokiol-based small molecules for their ability to disrupt the YAP-TEAD interaction.
• To evaluate the efficacy of identified compounds, particularly HK03, in preclinical melanoma models.

Main Methods:

• Utilized NanoLuc Binary Technology (NanoBiT) assay for protein-protein interaction screening.
• Assessed Cyr61 levels, Erk and Akt phosphorylation in B16-F10 melanoma cells.
• Evaluated epithelial-mesenchymal transition (EMT) and cell migration using wound-healing assays.
• Tested efficacy in a B16-F10 lung metastasis mouse model.

Main Results:

• Identified several honokiol analogues that disrupt YAP-TEAD interaction, with HK03 being the most potent.
• HK03 significantly reduced Cyr61 levels and phosphorylation of Erk and Akt.
• HK03 inhibited EMT and melanoma cell migration.
• In vivo administration of HK03 markedly reduced lung metastasis in mice.

Conclusions:

• Honokiol derivatives, exemplified by HK03, effectively target the YAP-TEAD axis in melanoma.
• HK03 demonstrates significant preclinical efficacy in reducing melanoma cell migration and metastasis.
• HK03 represents a promising lead compound for developing novel melanoma therapeutics.