A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action

• Published in: Angewandte Chemie International Edition Vol. 59; no. 13; pp. 5284 - 5287
• Main Authors: Gigante, Alba, Sijbesma, Eline, Sánchez‐Murcia, Pedro A., Hu, Xiaoyu, Bier, David, Bäcker, Sandra, Knauer, Shirley, Gago, Federico, Ottmann, Christian, Schmuck, Carsten
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 23.03.2020; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: 14-3-3; 14-3-3 Proteins - chemistry; Amino Acid Motifs; Amino Acid Sequence; Arginine; Arginine - chemistry; Binding; Breast cancer; Breast Neoplasms - metabolism; Communication; Communications; Computer applications; ERα; Estrogen Receptor alpha - chemistry; Estrogens; Glycosides - chemistry; Humans; Mode of action; Molecular Dynamics Simulation; Natural products; Peptides - chemistry; Protein Binding; protein-protein interaction; Proteins; Regulators; Selectivity; stabilizers; supramolecular systems; 14-3-3; supramolecular systems; protein-protein interaction; ERα; stabilizers
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201914517

We report on a stabilizer of the interaction between 14‐3‐3ζ and the Estrogen Receptor alpha (ERα). ERα 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 14‐3‐3ζ/ERα 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 ERα‐derived phosphopeptide. Furthermore, 1 shows selectivity towards 14‐3‐3ζ/ERα interaction over other 14‐3‐3 client‐derived phosphomotifs. These data provide a solid support of a new binding mode for a supramolecular 14‐3‐3ζ/ERα PPI stabilizer. A stabilizer of the interaction between the Estrogen Receptor alpha (ERα), a driver in the majority of breast cancers, and 14‐3‐3ζ, a negative regulator of ERα, is developed as anti‐cancer strategy. The stabilizer of this protein‐protein interaction (PPI) consists of three symmetric peptidic arms and stabilizes the 14‐3‐3ζ/ERα interaction synergistically with the natural product Fusicoccin‐A.