Discovery of Cyclic Peptides Targeting the BRAF Dimer Interface as Dual Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAF dimerization drives oncogenic signaling in RAS-mutant tumors.
• This dimerization contributes to resistance against mitogen-activated protein kinase (MAPK) pathway inhibitors.
• BRAF mutations (e.g., BRAF^V600E) and inhibitors like vemurafenib can cause paradoxical ERK signaling activation, a key resistance mechanism.

Purpose of the Study:

• To develop novel peptide inhibitors targeting BRAF dimerization.
• To overcome limitations of existing peptide inhibitors, such as poor cell permeability and cytotoxicity.
• To create dual-function peptides with both anti-dimerization and anti-invasion capabilities.

Main Methods:

• Design and synthesis of linear and cyclic peptides derived from Braftide, based on BRAF homodimer crystal structure.
• Evaluation of cell membrane permeability and serum stability of novel peptides.
• Assessment of anti-proliferative, anti-invasion, and anti-tumor effects in vitro and in vivo (A549 mouse xenograft model).

Main Results:

• CBF-2-2 demonstrated cell membrane permeability without CPPs and enhanced serum stability compared to Braftide.
• SCBF-2-2, a composite peptide, effectively disrupted BRAF dimers.
• SCBF-2-2 inhibited cancer cell proliferation and invasion, reduced ERK phosphorylation, and suppressed tumor growth in vivo.

Conclusions:

• SCBF-2-2 represents a novel dual-function peptide targeting BRAF dimers.
• This peptide effectively inhibits cancer cell proliferation, invasion, and tumor growth.
• SCBF-2-2 provides a new foundation for developing advanced antitumor peptide therapeutics.