14-3-3: A Case Study in PPI Modulation

Abstract

In recent years, targeting the complex network of protein–protein interactions (PPIs) has been identified as a promising drug-discovery approach to develop new therapeutic strategies. 14-3-3 is a family of eukaryotic conserved regulatory proteins which are of high interest as potential targets for pharmacological intervention in human diseases, such as cancer and neurodegenerative and metabolic disorders. This viewpoint is built on the “hub” nature of the 14-3-3 proteins, binding to several hundred identified partners, consequently implicating them in a multitude of different cellular mechanisms. In this review, we provide an overview of the structural and biological features of 14-3-3 and the modulation of 14-3-3 PPIs for discovering small molecular inhibitors and stabilizers of 14-3-3 PPIs.

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

“…Further support for our molecular model was obtained from a derivative of 1 where its GCP motifs were replaced by Lys (2), which resulted in a decrease of activity (80-to 12-fold stabilization, Figure 5), illustrating the importance of the GCP motif. Additionally, replacing the Phe and Lys residues in the peptidic side chains of 1 by Ala (3 and 4) also resulted in a drop of stabilization (20-and 14-fold stabilization, Figure 5).…”

“…Members of the 14-3-3 protein family are regulatory adapter elements in intracellular signaling pathways by means of recognition of proteins that contain phosphorylated Ser/Thr residues like those implicated in the MAPK (mitogen-activated protein kinase) pathway. [1,2] As a measure of their relevance, more than 300 potential binding partners of this family have been identified. Many of these have been shown to be involved in disease.…”

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

“…Members of the 14‐3‐3 protein family are regulatory adapter elements in intracellular signaling pathways by means of recognition of proteins that contain phosphorylated Ser/Thr residues like those implicated in the MAPK (mitogen‐activated protein kinase) pathway . As a measure of their relevance, more than 300 potential binding partners of this family have been identified.…”

Chemically stable inhibitors of 14-3-3 protein–protein interactions derived from BV02

“…To date, more than 500 partners of 14-3-3 have been identified through biochemical and bioinformatics studies, most of which are disease-relevant phosphorylated proteins sharing the optimal binding sequence R(X)XpS/TXP 1 . In recent years, 14-3-3 proteins have emerged as profitable targets in the therapy of several diseases including different types of cancer, neurodegenerative disorders, and pathogens infections [1][2][3][4] . In humans, seven different isoforms have been characterised, which are commonly named with Greek letters r, f, b, c, g, e, and s 5,6 .…”