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Department of Chemical Engineering and Biotechnology

 
Nature Communications paper for JJ Phillips

The modus operandi in much of medicine is first to determine the key mechanism of a disease process and then to use a drug to inhibit it.

Therefore, on a molecular level, there is often an entity that has an activity that we may wish to turn off. This molecule is termed the ‘drug target’ and a huge amount of effort is made in scientific research and in the pharmaceutical industry to accurately identify these valuable potential weak spots in diseases, such as cancers.

Protein kinases are considered to be the second most important group of drug targets (after G-protein-coupled receptors). The simplest method of drug action against this ubiquitous family of molecules is to bind to a highly conserved pocket, called the ‘active site.’

The key challenge is how to design the drug to specifically bind to just one member of this family. The answer lies in the fact that a protein kinase is not a static structure: it is highly dynamic and occupies (at least) three distinct postures. One of these – the so-called ‘DFG-out’ posture exposes its unique features and this is the form of the protein that must be targeted to design a useful medicine.

Recent work at the CEB Department by JJ Phillips, in collaboration with MedImmune and AstraZeneca, has yielded major insight into the structural dynamics of these kinases. In a paper to Nature Communications (DOI: 10.1038/ncomms8877), they focus on the Fibroblast Growth Factor Receptor 1 (FGFR-1) kinase domain. This protein is heavily implicated in the development of blood vessels in a number of tumour types, including breast, pancreatic, prostate and ovarian cancers. As such, it is a valuable target in cancer research - however, it is highly resistant to adopting this druggable ‘DFG-out’ posture.

This study dissects how the natural, unstimulated activity of the protein is linked to its molecular dynamics in detail resolved at high spatial resolution. This provides a rationale for why FGFR-1 kinase so rarely adopts a druggable state and has proved to be one of the most elusive of high-profile targets in cancer research.

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