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H2020Individual fellowship2016–2018

TaGFrag · Stabilising Protein-Protein Interactions: A Target-Guided Fragment-Based Approach

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2016-10-01 → 2018-09-30
EU contribution
€165,599
Participants
1
Scheme
MSCA-IF

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Results in brief

Stabilising Protein-Protein Interactions: A Target-Guided Fragment-Based Approach

The TaGFrag project aimed to discover novel, synthetically tractable small-molecule stabilisers of the therapeutically important 14-3-3σ – estrogen receptor alpha (ERα) protein-protein interaction (PPI). PPI stabilisation is an emerging strategy in drug discovery with the potential to deliver new medicines for the treatment of diseases such as cancer which pose a major societal challenge in Europe and beyond. Despite this potential it has been an under-explored approach in pharmaceutical research. This action set out to develop a rational target-guided chemical biology approach combining the concepts of fragment-based drug discovery (FBDD) with bioorthogonal synthesis. It sort to provide valuable tool or lead compounds to aid the maturation of this interaction as a clinical target and provide a rational and efficient approach for the discovery of PPI stabilisers in general. Early results prompted a change in focus to the 14-3-3σ – p53 PPI which was also of great pharmaceutical interest because of its potential as a drug target for cancer treatment. FBDD screening led to the identification of novel fragment compounds binding to the 14-3-3σ – p53 PPI interface, a crucial first step toward functional molecules. The development of new bioorthogonal chemistry approaches led to the discovery of fusicoccin A (FC-A) as the first small molecule stabiliser of this PPI thus providing an important starting point for rational drug design. During the project it was also observed that different length peptides used to mimic the p53 binding motif had very different binding properties. This had significant fundamental implications for how PPI stabilisation is studied in vitro and so was also pursued as a research avenue.

Data: CORDIS, © European Union

Project objective

This action aims to discover novel, synthetically tractable small-molecule stabilisers of the therapeutically important 14-3-3δ – estrogen receptor alpha (ERα) protein-protein interaction (PPI). To achieve this a rational target-guided chemical biology approach will be developed that combines the concepts of fragment-based drug discovery with bioorthogonal synthesis. The significances of achieving this aim are two-fold. First, it would provide valuable tool or lead compounds to aid the maturation of this interaction as a clinical target. Secondly, it would provide a rational and efficient approach for the discovery of PPI stabilisers in general. This under-explored area of pharmaceutical research has the potential to deliver new medicines for the treatment of diseases such as cancer which pose a major societal challenge in Europe. The project will combine the powerful tools of synthetic chemistry, biophysical assay techniques and protein crystallography in the true ethos of chemical biology for drug discovery. It will provide the Fellow with excellent experimental training in this increasingly important field, complimenting his proven track-record in synthetic organic chemistry research. Therefore this proposal seeks support to embark on an innovative, integrated and multidisciplinary programme of research which will allow for the consolidation and expansion of the experiences gained by the Fellow during his brief tenure at the ideally suited Laboratory of Chemical Biology, the Technical University of Eindhoven (TU/e). This Fellowship is a crucial opportunity to enhance the Fellow’s creative and innovative potential thus allowing him to establish an independent research career at the interface of synthetic chemistry and the study of biological systems.

Original text from CORDIS.

Participants

  • TECHNISCHE UNIVERSITEIT EINDHOVEN · EindhovenCoordinatorNetherlands

Links

Data: CORDIS, © European Union