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Protein ‘map’ could lead to potent new cancer drugs

Posted on 26 September 2014

Scientists at the University of York are part of a team of researchers which has gained fresh insights into how a disease-causing enzyme makes changes to proteins and how it can be stopped.

Enyzme N-myristoyl transferase with a bound substrate

The scientists in York Structural Biology Laboratory (YSBL) in the University’s Department of Chemistry hope their findings will help them to design drugs that could target the enzyme, known as N-myristoyltransferase (NMT), and potentially lead to new treatments for cancer and inflammatory conditions.

Working with colleagues at Imperial College London, they have already identified a molecule that blocks NMT’s activity, and have identified specific protein substrates where this molecule has a potent impact.

NMT makes irreversible changes to proteins and is known to be involved in a range of diseases including cancer, epilepsy and Alzheimer’s disease.

In a study published in the journal Nature Communications the researchers used living human cancer cells to identify more than 100 proteins that NMT modifies, with almost all these proteins being identified for the first time in their natural environment.

The scientists mapped all the proteins and also established that a small drug-like molecule can block the activity of NMT as well as inhibiting its ability to modify each of these proteins, suggesting a potential new way to treat cancer.

Professor Tony Wilkinson, of YSBL, said: “This is a wonderful example of the power of chemical biology - using chemistry to unravel biological problems and open up new avenues to therapy in human disease.”

The researchers spent several years developing a specialised set of tools to identify and examine NMT and the proteins it changes. They began by conducting a detailed large scale study exploring proteins under the control of NMT, but the scientists still needed information on the function of these proteins and how they are modified.

Next they used mass spectrometry to quantify the effect of a NMT inhibitor molecule. To examine this interaction, they induced a process called apoptosis, which programmes a cell to die - for example because its DNA has been damaged. This process is essential in cancer chemotherapy, and is often deactivated in drug resistant cancers. Until now scientists knew that NMT modified only a handful of proteins during apoptosis, but the results of this study identified many new proteins affected by NMT, suggesting new ways to combat drug resistance.

Professor Ed Tate, of the Department of Chemistry at Imperial who led the study, added: “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. We are still at an early stage in our research but we have already identified several very potent drug-like NMT inhibitors that are active in animal disease models, and we hope to move towards clinical trials over the next five to ten years.”

The research was funded primarily by Cancer Research UK and the Biotechnology & Biological Sciences Research Council, with further support from the Medical Research Council, the Engineering and Physical Sciences Research Council, and the European Union.

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