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For the field of cancer biology, designing drugs against a molecule that many deem ‘undruggable’ has seemed like a distant possibility.

But scientists don’t give up easily.

The molecule in question is called Myc. And it’s is a powerful controller, switching genes on and off to dictate when cells live, die or multiply.

It’s also frequently faulty in cancer, with close to seven out of ten cancers carrying overactive versions of this molecule. Switching Myc off looks a promising tactic for treating many cancers, but its complex characteristics have made it tricky to target with drugs.

Myc doesn’t work alone; it has a molecular partner in crime, called Aurora-A. So what if there was a way to get at Myc by disrupting this destructive duo? That’s a tantalising possibility, and one that could be drawing closer thanks to new research published in Proceedings of the National Academy of Sciences.

Using imaging techniques to zoom in on this pair, our scientists have worked out how they stick to one another to keep Myc stable, allowing it to fuel cell growth.

And by revealing this molecular ‘sweet spot’, our scientists could have a promising drug target on their hands.

Finding Myc’s crutch

“Unlike most protein molecules, Myc doesn’t have a defined 3D shape that we could design targeted drugs to fit into,” says lead researcher Professor Richard Bayliss from the University of Leeds.

“So instead the strategy is to try and target Myc’s interactions with other molecules.

“Myc doesn’t have a defined 3D shape that we could design targeted drugs to fit into”

– Professor Richard Bayliss

“And our work gives us the confidence that this can be done.”

Myc is actually a family of three relatives – c-Myc, N-Myc and L-Myc – that all play incredibly important jobs in the cell.

In many cancers, genetic faults can cause Myc to become overactive, ultimately allowing cells to grow out of control. Overactive N-Myc is often the driving force behind neuroblastoma and medulloblastoma – two of the most common tumours in children.

But Myc isn’t solely to blame. To do its job, Myc needs a helping hand from Aurora-A, a molecule that helps cells divide.

Myc is a bit like a long, wobbly bridge. Unless that bridge gets some structural support, it’ll fall down. And that’s where Aurora-A steps in, acting like a scaffold that prevents N-Myc from toppling over.

And while researchers knew that this troublesome relationship was going on inside cancer cells, how precisely the pair interact was a mystery.

Making things crystal clear

To get to the details of the interaction, the team used a sophisticated technique known as x-ray crystallography. This involves turning the molecules into crystals, bombarding them with x-rays and then analysing the resulting patterns of light to work out the molecules’ shape.

This precise technique allowed Dr Mark Richards, a scientist in the Bayliss group, to discover that the exact spot where N-Myc and Aurora-A touch overlaps with another important region on N-Myc. When a cell no longer needs N-Myc, the molecule gets tagged with a ‘sorting label’ exactly in that spot, which directs N-Myc for disposal. By getting in the way of these instructions, Aurora-A allows excessive amounts of N-Myc to build up, fuelling cell growth.

“We revealed the ‘holes’ on the surface of Aurora-A that N-Myc binds to,” says Bayliss. “So if you can block these holes with something, then perhaps you can disrupt this interaction.

“That’s what we’re trying to do now, working out which are the best holes to target and looking for molecules that can fill them in.”

An accidental helping hand

So if Myc is notoriously tricky to tackle, why not take Aurora-A out instead?

It’s not that simple. Assisting Myc is just one of Aurora-A’s jobs – its main role is to help cells to divide, which our bodies need to make new cells throughout life. That means any drugs that completely stop Aurora-A from working would likely have unwanted side effects.

But there are many parts to Aurora-A, and it turns out that the bit needed for its job in cell division – the ‘active site’ – isn’t the same part that stabilises N-Myc. Scientists have already developed drugs that block Aurora-A’s active site, which interested Bayliss and his team.

Dividing cell

Aurora-A helps cells to divide.

“Aurora-A is very well characterised, and there are lots of available ‘active site’ drugs,” he says.

“None of these were designed to target its interaction with N-Myc, but quite fortuitously one of them – Alisertib, which is now in clinical trials – happens to target both.”

This presented Bayliss and his team with an exciting opportunity.

“We wanted to understand how exactly Aurora-A interacts with N-Myc, and what happens when this drug, Alisertib, comes between them. Because that knowledge could help us design better drugs that could potentially be used in the clinic.”

What they found by studying the crystals was that, unlike the other active site drugs, Alisertib physically distorts Aurora-A. This twisted the part of Aurora-A that N-Myc normally fits into, preventing the two from interacting.

But as Alisertib also blocks Aurora-A’s active site, so there is room for improvement. And Bayliss hopes to accomplish those improvements through further research.

The beginning of the road

If researchers are successful in developing a drug that breaks up Aurora-A and N-Myc’s friendship, without blocking Aurora-A’s normal job in cell division, it could be turned into a potential treatment for neuroblastoma and medulloblastoma.

And recent research has also revealed that chasing Aurora-A’s role as a Myc stabiliser could have potential that extends further than these two diseases.

“This year a study showed that Aurora-A is important for stabilising N-Myc’s sibling, c-Myc, in liver cancer,” says Bayliss.

“There’s a lot of science to be done”

– Professor Richard Bayliss

“And we know that the interaction between Aurora-A and c-Myc involves regions that are very similar between N-Myc and c-Myc.

“So although we only know about the potential benefit of breaking up Myc and Aurora A in these three types of cancer, it could be that Myc is stabilised in this way in many other cancers.”

But Myc is complex, says Bayliss, and we don’t yet have enough information to know what might happen in patients if we try to block it.

“We need to find methods to attack Myc in different ways,” he adds. “But once we have those tools, we can ask the question: how do we go from interesting biology and challenging chemistry to applying these findings to treat patients?

“There’s a lot of science to be done, and it’s a long road to discovery. But it has to start somewhere.”


Richards, M. W. et al. 2016. Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors. PNAS.


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