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Details of Grant 

EPSRC Reference: EP/R00899X/1
Title: Molecular Switches as Sensors for Kinase Activity
Principal Investigator: Thomson, Dr A
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department: School of Chemistry
Organisation: University of Glasgow
Scheme: First Grant - Revised 2009
Starts: 01 November 2017 Ends: 31 October 2019 Value (£): 98,151
EPSRC Research Topic Classifications:
Biological & Medicinal Chem.
EPSRC Industrial Sector Classifications:
No relevance to Underpinning Sectors
Related Grants:
Panel History:
Panel DatePanel NameOutcome
13 Sep 2017 EPSRC Physical Sciences - September 2017 Announced
Summary on Grant Application Form
The goal of this study is to develop a new class of molecule that can report back on important biological processes as a tool for scientists designing new drugs. Biology uses various types of protein to pass signals around a cell, allowing the cell to respond to its environment. One such signalling mechanism is the addition of a phosphate group to a protein, and this process is carried out by a class of proteins called 'kinases'. Some diseases, including cancer, can come about in part because the signalling mechanism in a cell has become faulty, for example telling it to grow when it should not. Because of this, kinase enzymes are an attractive target for new drugs. Medicinal chemists are designing small molecules that can shut down specific kinases, and therefore prevent their signal from being passed on. This has the potential to switch off the broken signalling mechanisms in a diseased cell. Unfortunately, measuring the activity of a kinase is not straightforward, so it is a difficult and time-consuming process to know whether or not a new drug will be effective at inhibiting a specific kinase. We will help to solve this problem by developing a molecule that will act as a reporter of how active a given kinase is, therefore speeding up the process of searching for kinase inhibitors. This reporter molecule will work in a unique way: it will change shape when a kinase adds a phosphate group to it, and the change in shape will bring about a fluorescent signal that can be detected with standard laboratory instruments. This is possible because the reporter molecule is a 'peptide', built from the same building blocks as the proteins that the kinase would normally add a phosphate group to. The sensor will work because it has a central core that can exist in two distinct shapes: one stretched out, and one in which the molecule is folded back on itself. When it doesn't have a phosphate group, the sensor will exist predominantly in the stretched out state. When the kinase adds a phosphate group to it, however, the sensor will fold back on itself so that it can wrap around the phosphate group. This folded form will bring two special fluorescent groups close together in space, allowing them to produce a signal that can be easily detected with standard lab instruments. The result of this is that the amount of signal produced by the sensor will depend on the ability of the kinase to add a phosphate group to it. This means that a scientist will be able to conduct a screen where they look for small molecules that inhibit a kinase simply by looking for conditions in which the kinase is prevented from switching the sensor to the 'on' state. Rapid screens of this sort are vitally important in the search for new drugs because the number of potential drug molecules is huge. In the case of kinase inhibitors for the treatment of cancer it is also necessary to consider that the kinases themselves can mutate, causing a cancer to become resistant to a drug. By speeding up the screening process it will become possible to search for new drugs more quickly, and to better understand how changes to individual kinases can affect their response to existing drugs. This will help clinicians to tailor their treatments to a patient's specific illness- so called 'personalised healthcare'. In the case of cancer this will help doctors to be one step ahead of the mutations that can cause a tumour to become drug resistant, allowing them to make better informed choices of which drugs to use, resulting in more-effective treatments.
Key Findings
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