Researchers at Imperial College London say they have gained new insights into how a disease-causing enzyme makes changes to proteins and how it can be stopped. The scientists hope their findings will help them design drugs that could target N-myristoyltransferase (NMT) and potentially lead to novel therapies for cancer and inflammatory conditions.

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 (“Global profiling of co- and post-translationally N-myristoylated proteomes in human cells”) published in Nature Communications, chemists 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 environment. The scientists mapped all of the proteins and also 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 way to treat cancer.

“Quantitative dose response for inhibition of N-myristoylation is determined for more than 70 substrates simultaneously across the proteome,” wrote the investigators. “Small molecule inhibition through a conserved substrate-binding pocket is also demonstrated by solving the crystal structures of inhibitor-bound NMT1 and NMT2. The presented data substantially expand the known repertoire of co- and post-translational N-myristoylation in addition to validating tools for the pharmacological inhibition of NMT in living cells.”

“We now have a much fuller picture of how NMT operates, and more importantly how it can be inhibited, than ever before,” said lead researcher Ed Tate, Ph.D., from the college’s department of chemistry. “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.”

It is expected that the global map will allow scientists to understand what the effects of inhibiting NMT will be. This means researchers will be able to determine which diseases it might be possible to combat by targeting NMT, enabling them to explore how effective such treatments could be, added Dr. Tate.

The researchers spent several years developing a specialized 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 apoptosis, which is essential in cancer chemotherapy and is very 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.

“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,” noted Dr. Tate. “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.” 

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