14-3-3 Protein-Protein Interactions: From Mechanistic Understanding to Their Small-Molecule Stabilization

Protein-protein interactions (PPIs) are of utmost importance for maintenance of cellular homeostasis. Herein, a central role can be found for 14-3-3 proteins. These hub-proteins are known to bind hundreds of interaction partners, thereby regulating their activity, localization, and/or stabilization. Due to their ability to bind a large variety of client proteins, studies of 14-3-3 protein complexes flourished over the last decades, aiming to gain greater molecular understanding of these complexes and their role in health and disease. Because of their crucial role within the cell, 14-3-3 protein complexes are recognized as highly interesting therapeutic targets, encouraging the discovery of small molecule modulators of these PPIs. We discuss various examples of 14-3-3-mediated regulation of its binding partners on a mechanistic level, highlighting the versatile and multi-functional role of 14-3-3 within the cell. Furthermore, an overview is given on the development of stabilizers of 14-3-3 protein complexes, from initially used natural products to fragment-based approaches. These studies show the potential of 14-3-3 PPI stabilizers as novel agents in drug discovery and as tool compounds to gain greater molecular understanding of the role of 14-3-3-based protein regulation. Molecular glues that stabilize the interaction of the phosphorylation reader protein 14-3-3 with individual client proteins present a huge opportunity for therapeutic intervention in a wide array of human diseases. Among the vast array of 14-3-3 clients are disease-related proteins like LRRK2, Tau, p53, C-Raf, CFTR, Pyrin, PLN, and ChREBP, where a 14-3-3 molecular glue promises a therapeutic benefit for patients. image