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

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Abstract RAF dimerization is crucial for oncogenic signaling in RAS mutant tumors, contributing to resistance to mitogen-activated protein kinase pathway inhibitors by promoting dysregulated BRAF dimerization. This makes it a promising target for overcoming resistance caused by paradoxical extracellular signal-regulated kinase (ERK) signaling activation resulting from BRAF mutations (e.g., BRAFV600E) and inhibitors like vemurafenib and dabrafenib. Peptide inhibitors such as Braftide (TRHVNILLFM) block BRAF dimerization but lack cell permeability and biological activity within cells. A promising solution is conjugating cell-penetrating peptides (CPPs). However, this approach involves a trade-off: it produces a larger molecule and increases the level of off-target cytotoxicity. On the basis of the crystal structure of the BRAF homodimer, we developed a series of linear and cyclic peptides derived from Braftide. Among these peptides, CBF-2-2 crosses the cell membrane without the aid of CPPs and significantly inhibits tumor cell growth, exhibiting greater serum stability than Braftide. Moreover, the composite peptide SCBF-2-2, which contains an anti-invasion sequence, disrupts BRAF dimers, effectively inhibits cancer cell proliferation and invasion, reduces ERK phosphorylation, and suppresses tumor growth in the A549 mouse xenograft model. SCBF-2-2 offers a new starting point for developing dual-function antitumor peptides that target the BRAF dimer.

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