Protein Maps to Help Develop Powerful New Cancer Drugs

Chemical scientists have gained new insights into how a disease-causing enzyme makes changes to proteins and how to block it. The scientists hope their findings will help them to design drugs that could target the enzyme, known as N-myristoyltransferase, and potentially lead to new treatments for cancer and inflammatory conditions.

The scientists 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 September 28, 2014, in the journal Nature Communications, biochemists used living human cancer cells to identify more than 100 proteins that NMT modifies, with almost all these proteins being identified for the very first time in their natural setting. The scientists mapped all of the proteins and in addition ascertained that a small drug-like molecule can block the activity of NMT and suppress its ability to modify each of these proteins, suggesting a potential new way to treat cancer.

Lead researcher Prof. Ed Tate, from the department of chemistry at Imperial College London (UK), 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. This ‘global map’ allows us 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.”

The researchers spent several years developing a dedicated set of tools to identify and examine NMT and the proteins it changes. They began by conducting a detailed large scale study searching for proteins under the control of NMT, but the scientists still needed data 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 apoptosis. This process is crucial in cancer chemotherapy, and is very frequently deactivated in drug-resistant tumors. Up to now, scientists knew that NMT modified only a handful of protein during apoptosis, but the findings of this study identified many new proteins affected by NMT, suggesting new ways to combat drug resistance.

Pondering on the next phase of research, Prof. Tate said, “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 10 years.”

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Imperial College London