New Therapeutic Approach for Targeting Hippo Signalling Pathway

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Nuclear localization signals (NLS) facilitate protein import into the cell nucleus.
• The Hippo signaling pathway, involving TEAD and YAP transcription factors, is frequently deregulated in various cancers.
• Targeting protein-protein interactions within the nucleus is a promising strategy for anti-cancer drug development.

Purpose of the Study:

• To design and validate a novel chimeric peptide for targeted nuclear delivery.
• To investigate the anti-cancer efficacy of this peptide by blocking TEAD-YAP interactions.
• To assess the therapeutic potential of the peptide in preclinical cancer models.

Main Methods:

• Construction of a tri-functional peptide combining a cell-penetrating peptide (CPP), an NLS, and a TEAD-YAP interaction inhibitor.
• Validation of peptide cell penetration and nuclear localization using flow cytometry and fluorescence microscopy.
• Assessment of apoptotic effects in tumor cell lines and anti-tumoral activity in vivo using breast cancer xenograft models.

Main Results:

• The chimeric peptide successfully penetrated cell membranes and localized to the nucleus.
• The peptide induced apoptosis in cancer cell lines by inhibiting the TEAD-YAP interaction.
• Significant tumor growth inhibition was observed in vivo in preclinical breast cancer models.

Conclusions:

• The developed chimeric peptide effectively delivers its cargo to the nucleus, targeting oncogenic protein-protein interactions.
• This peptide exhibits potent anti-cancer activity both in vitro and in vivo.
• The findings support the development of this peptide as a novel nuclear anti-neoplastic drug.