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

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.

Call for proposal

FP7-PEOPLE-2011-IAPP
See other projects for this call

Funding Scheme

MC-IAPP - Industry-Academia Partnerships and Pathways (IAPP)

Coordinator

TECHNISCHE UNIVERSITEIT EINDHOVEN
Address
Groene Loper 3
5612 AE Eindhoven
Netherlands
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 614 416
Administrative Contact
Leon F. Luwijs (Mr.)

Participants (4)

LEAD DISCOVERY CENTER GMBH
Germany
EU contribution
€ 779 339
Address
Otto Hahn Strasse 15
44227 Dortmund
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Administrative Contact
Michael Hamacher (Dr.)
MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany
EU contribution
€ 180 277
Address
Hofgartenstrasse 8
80539 Munchen
Activity type
Research Organisations
Administrative Contact
Barbara Dobruchowski (Ms.)
CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France
EU contribution
€ 227 360
Address
Rue Michel Ange 3
75794 Paris
Activity type
Other
Administrative Contact
Gilles Pulvermuller (Mr.)
UMEA UNIVERSITET
Sweden
EU contribution
€ 207 230
Address
Universitetomradet
901 87 Umea
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Ethel Strömdahl (Ms.)