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Small molecule stabilizers of 14-3-3 Protein-Protein Interactions as novel drugs in cancer and neurodegenerative diseases (14-3-3Stabs)
Date du début: 1 janv. 2012, Date de fin: 31 déc. 2015 PROJET  TERMINÉ 

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/TAZ2. 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.



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