Feature: Centre for Kinomics shakes up drug discovery

It was undoubtedly an exceptional week for Adam McCluskey, Phillip Robinson and Roger Reddel. Following hot on the heels of the three receiving a $1 million prize from the Ramaciotti Foundation came another $3.1 million from the Australian Cancer Research Foundation (ACRF). $4.1 million in the space of a few days. “How’s that for a good week?” remarks Robinson.

This combined funding will allow them to realise a dream concocted by McCluskey and Robinson to create the world’s first centre focusing on the emerging field of kinomics. Once the centre is in full flight, they hope it’ll do nothing less than revolutionise the study of protein kinases and the drugs that target them. Or, in the words of McCluskey, they expect it’ll open ‘Pandora’s box’ for drug discovery.

Collaborative ventures

The Centre for Kinomics – or ‘ACRF Chemical Proteomics Centre for Kinomics supported by the Ramaciotti Foundation’, to go by its full title – is the product of more than a decade of fruitful collaboration between McCluskey and Robinson, and is an idea that lies at the intersection of their specialties.

Professor Phil Robinson is based at the Children’s Medical Research Institute (CMRI) at Westmead in Sydney, which is run by Professor Roger Reddel. Robinson has spent nearly 30 years investigating proteins and signalling, particularly protein phosphorylation and protein kinases. His recent focus, in collaboration with McCluskey, has been on the role of kinases in controlling synaptic transmission.

Adam McCluskey, who is Professor in Chemistry at the University of Newcastle, has used the insights gained by Robinson’s research into the signalling mechanisms at work in synapses to design drugs that can modify the behaviour of these mechanisms. Over the past decade, the two have investigated a range of diseases but have recently focussed their efforts on epilepsy, a disorder where one in three sufferers gain no relief from existing drugs, and have targeted one particular protein, dynamin.

While this research has proved highly fruitful – with progress made towards a drug that could reduce seizure rates in epilepsy sufferers as well as other drugs that show promise in reducing tumour growth in some cancers – it’s in the labours of developing these drugs that Robinson and McCluskey came up with their latest brainstorm.

“One of the things that’s always been at the back of our minds is: If you give someone a drug, there’s going to be side effects, and that’s one of the things that slows the drug development pathway down immensely,” says McCluskey. “You’ve got to try to figure out exactly where it’s hitting: is it hitting a good target or is it hitting a bad target? And, being brutally honest, I don’t think there’s any simple cost-effective, rapid way of doing that.”

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Kinobeads

Then, in 2007, along came a paper in Nature Biotechnology by Marcus Bantscheff and Dirk Eberhard and their group from Cellzome AG, a private drug discovery company based in Germany. This paper described a new technique for analysing the interactions between kinase inhibitors and hundreds of proteins at a time. “It took the world by storm,” says Robinson.

The technology described in Bantscheff et al. is called Kinobeads – a name that has been trademarked by Cellzome. Kinobeads are tiny latex beads with seven broad spectrum kinase inhibitors attached. These function as kinase capturing tools, each capable of binding to a couple of dozen or more kinases and other ATP- and purine-binding proteins; overall, more than 1,000 proteins bind to the Kinobeads.

The Kinobeads can then be introduced into a cell lysate along with the drug being investigated. The drug will then compete with the Kinobeads to bind with its target proteins, so the Kinobeads will end up binding with fewer of the proteins targeted by the drug. Mass spectrometry can determine what proteins have been fished out by the Kinobeads, indicating which kinases have remained bound to the drug in question.

It’s really a shrewd derivation of what biologists have been doing for years, says McCluskey. But instead of sticking a single inhibitor on a bead and fishing for a handful of proteins at a time, Kinobeads can sample a broad swathe of the kinome in one fell swoop.

“This is something that would normally take six or eight months to even contemplate doing,” says McCluskey. “But with the system we’re going to put in place, Phil reliably ensures me that the mass spec run will take about two hours and the analysis will take a little bit longer. Basically, you’re looking at doing in days what used to take weeks or years.”

Thus the idea for the Centre for Kinomics came from the meshing of McCluskey and Robinson’s work developing drugs to counter epilepsy and cancer and the innovation brought about by Kinobeads.

“We’d originally been looking at how we can we find out where our compounds hit to see if we can accelerate the drug process. And then there was this other group that came out and said ‘We have this technology for looking at things very quickly’. We put two and two together and we came up with about 18 at the last count,” says McCluskey.

Robinson and McCluskey are intending to take the Kinobead technology and kick it up a notch by modifying the chemistry of the beads themselves. They’ll do this by using click chemistry to customise the beads, giving researchers a vast amount of flexibility in how they use them.

“By going down the click route, basically what we’re assembling is a kit,” says McCluskey. “So we can have the beads already prepared and ready for the compounds to be attached. We can also have all of the individual kinase inhibitors basically sitting in a drawer. Depending on what our research collaborator wants we can go in to the drawer and pick out whichever kinase inhibitors are required and then click them on to the beads. It’s an incredible amount of versatility.”

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Go with the flow

The first step in the process of getting the Centre off the ground is actually making the beads. “The chemistry underpins everything that comes after it,” says McCluskey. “If we don’t have the beads, we can’t do the kinomics. So we have to make sure that the systems are fully up and running and that we’ve optimised the chemistry.”

This is where the ACRF and Ramaciotti grants come in. The money will go towards building an advanced flow chemistry facility – the first of its kind in Australia – to be located at the University of Newcastle.

McCluskey is enthusiastic about the possibilities for rapid and efficient fabrication of the beads using flow chemistry. Instead of producing compounds in multiple steps using batch chemistry, the new flow chemistry facility will allow him to output large quantities of the desired product with flexible and easily scalable yields.

“With the flow chemistry we’ll build up a database of conditions that allow us to generate any material that we want for the Centre,” says McCluskey. “Then those materials will be produced on an ongoing basis, they’ll be stuck in a refrigerator, and when we get the request for a specific bead, we’ll then just click them on.”

He expects to have the first beads produced by mid-2010, but then he needs to characterise them and ensure they work as advertised. Once that’s completed, he hopes to have beads ready for researchers around the end of 2010.

The second step in the process is the advanced quantitative mass spectrometry – where half the money will be focused. It will analyse the results of the experiments using the beads. A custom mass spectrometry facility has already been built at the Children’s Medical Research Institute, where Robinson is based, so all that’s needed are the final pieces of equipment to get it off and running.

“If we hadn’t got this money, it would have been pretty sad, because the facility would be mostly empty,” says Robinson. “We built it determined to get this money. So it’s ready to fill. I’m working out orders to get it going now.”

The biggest hurdle, according to Robinson, is getting the people in place to staff the facility once it’s up and running.

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Opening the box

When it’s in full flight, however, McCluskey and Robinson are confident that it will make a big splash in terms of drug discovery in Australia.

“We believe that this will really boost scientific discovery,” says Robinson. “But our real hope – and the high risk in investing in us that the ACRF and Ramaciotti Foundation have both taken – is: will we come up with better drugs and better therapeutics for cancer patients and other indications? That’s our real hope.

“We hope to come up with a better understanding of what the targets and off-targets for current therapeutic drugs – particularly cancer therapeutics that target kinases –are and to be able to use that information, through the collaborators, to design better ways to get around those problems and improve the drug.”

McCluskey is just as optimistic. “When I said Pandora’s box, I meant it. The more I think about this, the more I can see it having an impact.”