Selectively Inhibiting MYC Oncogene Activation with Designed Peptides

Selective inhibition of oncogenes by artificial peptides is an increasingly attractive therapeutic strategy for treating cancer. In human cancers, the over-expression of the Myc transcription factor leads to tumorigenesis. Previous studies demonstrated that deactivation of the MYC oncogene resulted in tumor regression and a reversion of the tumor cells from a neoplastic to a fully differentiated state. Since Myc activation requires heterodimerization via coiled-coil domain interactions with Max, another member of the basic helix-loop-helix (bHLH) zipper protein family, we engineered dominant negative peptides that target this specific protein-protein interaction to inhibit Myc activation as an anti-neoplastic therapeutic strategy. The human dominant negative peptides were generated by replacing the basic DNA binding helix of Max with an acidic sequence which interacts with Myc's basic DNA binding helix to effectively disrupt its interaction with the DNA sequence necessary for Myc transcription. This acidic modification was made to the Max peptide and to "Winner," a peptide rationally designed to enhance interaction with Myc, resulting in peptides "aMax" and "aWinner." We show that the thermal stability of Myc:aWinner heterodimer is comparable to that of the Myc:aMax heterodimer, but with improved specificity for Myc. More importantly, aWinner decreased the levels of wildtype Myc:Max interaction and had an anti-proliferative effect when transfected into breast cancer cells. Together, these results indicate that aWinner is capable of inhibiting Myc activation and can be used as a potential anti-cancer drug.