A Supramolecular Stabilizer of the 14-3-3 zeta/ER alpha Protein-Protein Interaction with a Synergistic Mode of Action

We report on a stabilizer of the interaction between 14-3-3 zeta and the Estrogen Receptor alpha (ER alpha). ER alpha is a driver in the majority of breast cancers and 14-3-3 proteins are negative regulators of this nuclear receptor, making the stabilization of this protein-protein interaction (PPI) an interesting strategy. The stabilizer (1) consists of three symmetric peptidic arms containing an arginine mimetic, previously described as the GCP motif. 1 stabilizes the 14-3-3 zeta/ER alpha interaction synergistically with the natural product Fusicoccin-A and was thus hypothesized to bind to a different site. This is supported by computational analysis of 1 binding to the binary complex of 14-3-3 and an ER alpha-derived phosphopeptide. Furthermore, 1 shows selectivity towards 14-3-3 zeta/ER alpha interaction over other 14-3-3 client-derived phosphomotifs. These data provide a solid support of a new binding mode for a supramolecular 14-3-3 zeta/ER alpha PPI stabilizer.