Development of succinimide-based prodrugs of the NGR to iso-DGR transformation; new small molecule antimetastatic and immunotherapeutic agents
Dr Helen Sheldrake
Dr Steven Shnyder
Prof Paul Loadman
No more applications being accepted
Funded PhD Project (European/UK Students Only)
The integrins are a family of proteins found on the surface of cells which mediate communications with other cells and the surrounding environment. Changes in integrin expression are common in tumours since they control a number of processes involved in tumour growth, spread via the bloodstream, and interaction with bone. Therefore blocking integrin binding or signalling is likely to block tumour growth and spread through the body – providing a new and effective treatment of advanced cancers. However, no drugs targeting integrins have succeeded in the clinic – those developed so far can both deactivate and activate integrins which renders them ineffective as treatments.
Recently, it was discovered that part of a protein structure called the iso-DGR sequence, which binds to a specific part of the integrin, deactivates integrin functioning in a much more effective way than previously developed drugs. We have identified a small molecule structure which, when added to cells, reveals a new functional group and binds to the integrin in the same way as iso-DGR. This is potentially suitable for development into a new anticancer treatment.
This project aims to explore the molecule, demonstrating that it is able to deactivate integrin function in cancer cells. It will provide training in a broad range of skills and understanding of the drug discovery process, and is suitable for a student with a first degree in Chemistry and an interest in cancer research and/or drug discovery.
This is a University fully funded studentship covering stipend and UK/EU fees.
Sheldrake, H.M.; Patterson, L.H. Function and antagonism of beta3 integrins in the development of cancer therapy. Curr. Cancer Drug Targets 2009, 9, 519-540.
Corti, A.; Curnis, F.; Arap, W.; Pasqualini, R. The neovasculature homing motif NGR: more than meets the eye. Blood 2008, 112, 2628-2635