"Global protein map" targets cancer

A team of chemists from Imperial College London (ICL) has discovered how to stop a disease-causing enzyme, known as N-myristoyltransferase (NMT), from making life-threatening changes to proteins, and how to utilise the discovery in the development of new treatments for cancer and inflammatory conditions.

According to the researchers, they have already made ground in identifying a molecule that actively blocks NMT’s activity, and claim to have identified specific protein substrates where this molecule has a ’potent impact’.

“We can determine which diseases it might be possible to combat by targeting NMT

Lead researcher Ed Tate

To conduct the study, ICL chemists used living human cells to identify more than 100 proteins that NMT is capable of modifying, with almost all these proteins being identified for the first time in their natural environment.

Chemists then mapped each individual protein and established that a small drug-like molecule can block the activity of NMT and inhibit its ability to modify each of these proteins, suggesting a potential new method for treating cancer.

Lead researcher Ed Tate, from the Department of Chemistry at ICL, said: “We now have a much fuller picture of how NMT operates, and more importantly how it can be inhibited, than ever before.

“This is the first time that we have been able to look in molecular detail at how this potential drug target works within an entire living cancer cell, so this is a really exciting step forward for us.”

Tate said that the ’global map’ of proteins will allow researchers to understand what the effects of inhibiting NMT will be.

“This means we can determine which diseases it might be possible to combat by targeting NMT, enabling us a next step to explore how effective such treatments could be,” he said.

Once a specialised set of tools had been developed to identify and examine NMT and the proteins it changes, the research team conducted a detailed large scale study exploring proteins under the control of NMT.

Using mass spectrometry, the research team then attempted to quantify the effect of a NMT inhibitor molecule.

To examine this interaction, the team induced a state of apoptosis which programmes a cell to die - a process which is essential in chemotherapy, and is commonly deactivated in drug-resistant cancers, the researchers said.

Until now, scientists knew that NMT modified only a handful of protein during apoptosis, but the results of the ICL study identified a variety of new proteins affected by NMT, suggesting new ways to combat drug resistance.

“On the back of these results we are looking to test a drug that will have the most potent impact on blocking NMT’s ability to modify proteins, and we have started working with collaborators at the Institute of Cancer Research and elsewhere on some very promising therapeutic areas,” Tate said.

“We are still at an early stage in our research but we have already identified several very potent drug-like NMT inhibitors that are [very effective against cancer cells] and active in animal disease models, and we hope to move towards clinical trials over the next five to ten years.”

Speaking to LaboratoryTalk, Tate said the ICL team has some as yet unpublished evidence that NMT inhibition can also effectively control the inflammatory response.

“This may have a number of applications, for example in sepsis/toxic shock, or in autoimmune disorders, and could also limit inflammation that can contribute to progression of some cancers,” Tate said.

The research, which has been published in the journal Nature Communications, was carried out in collaboration with the University of York.