14-3-3STABS

Small molecule stabilizers of 14-3-3 Protein-Protein Interactions as novel drugs in cancer and neurodegenerative diseases

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 Obiettivo del progetto (Objective)

'The objective of the application is the development and characterization of small molecule stabilizers of protein-protein interactions (“Molecular Glues”) as a novel class of biological tool compounds and potential therapeutic drugs for the treatment of cancer as well as Alzheimer’s and Parkinson’s Disease, respectively. As biological targets we work on 14-3-3 proteins, an important class of adapter proteins that regulate a multitude of enzymes and proteins involved in the development of cancer and neurodegenerative diseases. 14-3-3 protein-protein interactions relevant in different cancers are Raf1 and YAP/TAZ. In Alzheimer’s and Parkinson’s Disease the interaction of 14-3-3 proteins with AICD and α-Synuclein are of potential therapeutic interest. The proposed project is based on the innovative approach to develop small molecules that bind selectively to the interaction surface of specific disease-related protein complexes thereby stabilizing their interaction which might lead to a beneficial therapeutic effect. This approach is complementary to today’s strategy of developing inhibitors that target the active site of single enzymes and opens new possibilities to address “undrugable targets”. In fact, small molecule stabilizers of protein-protein-interactions have the potential to deliver a target-specific, target-oriented and more efficient modulation of the protein function than “classical” inhibitors. In this application, we propose two projects identifying and optimizing small molecules stabilizing 14-3-3 interactions with:

1. The cancer-relevant proteins Raf and YAP/TAZ

2. The Alzheimer’s and Parkinson’s disease-relevant proteins AICD and α-Synuclein.

By stabilizing these protein-protein interactions the biological functions and biochemical properties like biochemical activity, subcellular localization and aggregation behaviour of the 14-3-3 target proteins are modulated.'

Introduzione (Teaser)

Finding novel targets to treat neurodegenerative disorders and cancer is an ongoing quest. A European initiative is working on a novel class of inhibitors.

Descrizione progetto (Article)

The family of 14-3-3 proteins is a unique group of small regulatory molecules that are present in all eukaryotic cells. They bind to serine/threonine-phosphorylated residues and regulate key proteins involved in various physiological processes such as intracellular signalling, cell cycle and programmed cell death.

Recent evidence indicates that they are also involved in the control of various enzymes and proteins implicated in cancer and neurodegenerative diseases. Detection of 14-3-3 proteins in the cerebrospinal fluid is used as a diagnostic indication of Creutzfeldt-Jakob disease (CJD) and other disorders.

Scientists on the EU-funded 14-3-3STABS project wish to explore 14-3-3 proteins as therapeutic targets. The project will focus on Alzheimer's and Parkinson's diseases and the interaction of 14-3-3 proteins with Tau and LRRK2. With respect to cancer, the work will investigate the interaction of 14-3-3 proteins with the oestrogen receptor alpha and the beta-catenin interacting protein CHIBBY.

14-3-3STABS proposes to develop small molecules that bind selectively to the interaction surface of specific disease-related protein complexes. The idea is that this could lead to a beneficial therapeutic effect by modulating the biological functions and biochemical properties of the 14-3-3 target proteins.

The advantage of this approach is the targeted specificity and higher efficiency compared to standard inhibitors.