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alpha-Helix Mimetics as Inhibitors of Protein-Protein Interactions Involved in Cancer Development and Progression


   Faculty of Biological Sciences

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  Prof A J Wilson  Applications accepted all year round  Competition Funded PhD Project (Students Worldwide)

About the Project

The purpose of this project is to develop a RULE-BASED APPROACH for the design and synthesis of inhibitors of key protein-protein interactions (PPIs) involved in the development and progression of cancer.

In order to effectively intervene in biological processes, it is necessary to inhibit protein-protein interactions (PPIs). However, it is difficult to design small molecules that cover 800-1100Å2 of a protein surface and complement the poorly defined projection functional groups on a flat or moderately convex surface. The project is concerned with the development of scaffolds that posses the required size and shape to cover the large discontiguous projection of functional groups found at protein-protein interfacess. These scaffolds will be amenable to rapid modular or dynamic synthesis. The student will have opportunities to develop, synthesise and test both novel aromatic oligoamides as proteomimetics. Current cancer targets include: p53/hDM2, Bcl-xL/BID, Mcl-1/NOXA-B, androgen receptor/co-activator interactions. Inhibitors of these targets are being sought to decrease tumour growth, with potential clinical applications in a broad range of cancers, including breast cancer, prostate cancer and small cell lung carcinoma.

This multidisciplinary project will provide opportunities for the student to receive training in organic synthesis in addition to molecular biology, molecular modelling and biophysical analysis. Significant opportunities exist to tap into active collaborations across the University of Leeds and beyond. This opportunity is associated a larger ERC starting investigator project led by Dr Andy Wilson Please contact Dr. Andy Wilson ([Email Address Removed]) for further details about this project.

Funding Notes

This project is being advertised under the Astbruy Centre WT 4 Year PhD program

References

1. D. J. Yeo, S. L. Warriner, A. J. Wilson: Monosubstituted Alkenyl Amino Acids for Peptide “Stapling”, Chem. Commun., 2013, 49, 9131-9133
2. V Azzarito, K. Long, N. S. Murphy and A. J. Wilson: Inhibition of a-Helix Mediated Protein-Protein Interactions Using Designed Molecules, Nature Chem., 2013, 5, 161-173
3. N. S. Murphy, P. Prabhakaran, V. Azzarito, J. P. Plante, M. J. Hardie, C. A. Kilner, S. L. Warriner, A. J. Wilson: Solid Phase Methodology for Synthesis of O-Alkylated Aromatic Oligoamide Inhibitors of α-helix Mediated Protein-Protein Interactions, Chem. Eur. J., 2013, 19, 5546-5550
4. F. Campbell, J. P. Plante, T. A. Edwards, S. L. Warriner, A. J. Wilson: N-Alkylated Oligoamide alpha-Helical Proteomimetics, Org. Biomol. Chem., 2010, 8, 2344-2351
5. J. P. Plante, T. Burnley, B. Malkova, M. E. Webb, S. L. Warriner, T. A. Edwards, A. J. Wilson: Oligobenzamide Proteomimetic Inhibitors of the p53-hDM2 Protein-Protein Interaction, Chem. Commun., 2009, 5091-5093
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