BRAF is the most frequently mutated kinase in human cancers and is one of the major effectors of oncogenic RAS. So BRAF is a target of interest for anti-cancer drug development and peptide inhibitors.

Two FDA-approved inhibitors, dabrafenib and vemurafenib have been developed as inhibitors for BRAF. These ATP-competitive inhibitors potently inhibit the most common BRAF variant V600E. However, current BRAF inhibitors could induce drug resistance and paradoxical activation. New approaches and drug candidates are needed to disrupt the intact dimer interface of BRAF. The 10-mer peptide inhibitor braftide was designed using a computational approach to block RAF dimerization. It was found that the peptide inhibitor triggers selective protein degradation of BRAF and MEK through proteasome-mediated protein degradation in cells.

The combination of ATP competitive inhibitors and braftide eliminates paradoxical activation. This alternative strategy will improve the efficacy of current ATP-competitive inhibitors. The RAF dimer interface could be a promising therapeutic target.

Braftide is a 10-mer peptide TRHVNILLFM. Braftide disrupts BRAF dimers and inhibits BRAF kinase activity. Braftide causes degradation of BRAF leading to destabilized MAPK complexes. Braftide synergizes with ATP-competitive inhibitors like Dabrafenib to mitigate paradoxical MAPK activation and downregulate MAPK signaling.

In this study, the Braftide, Null-Braftide, TAT-PEGlinker-Braftide, and TAT peptides were purchased from LifeTein with TFA removal.

Reference: ACS Chem Biol. 2019 Jul 19; 14(7): 1471–1480.