How Astex founder Dr Harren Jhoti has changed the drug discovery process
Cambridge Science Park company's first drug will help many breast cancer patients
Big isn’t always best.
Take medicines entering our bodies, for example. The larger and more complex the compound, the harder it is for it to interact with its target inside us. It’s a bit like trying to wedge a child’s puzzle shape into your 5,000-piece jigsaw.
Structural biologist Dr Harren Jhoti recognised that this was a major barrier to the creation of new drugs.
With Cambridge University’s Professor Sir Tom Blundell, from the Department of Biochemistry, and Professor Chris Abell, from the Department of Chemistry, he founded the company Astex in 1999 to explore an approach that would become known as ‘fragment-based drug discovery’.
It has dramatically changed how pharmaceutical companies do their work.
For his endeavours, Harren was given a Lifetime Achievement Award from the BIA, the UK BioIndustry Association, in January.
He is a fellow of the Academy of Medical Sciences, the Royal Society of Chemistry and the Royal Society of Biology. He was awarded the Prous Institute-Overton and Meyer Award by the European Federation for Medicinal Chemistry in 2012 and named World Entrepreneur of the Year for 2007 by the Royal Society of Chemistry.
And last month, he was made a fellow of the Royal Society.
But perhaps his proudest moment came last year when Kisqali, Astex’s first drug – developed in tandem with the pharmaceutical firm Novartis – was approved for patients with metastatic breast cancer in the European Union and United States.
“It was huge – a landmark achievement for the company,” he says. “That collaboration started in 2005. Not only does it take a long time, it’s actually very rare for companies to get a drug into the market.”
Kisqali has also been approved by NICE, the institute that determines which drugs will be available on the NHS.
“It’s one thing having it approved but to have a recommendation for it to be reimbursed, that was incredible. It is going to be helping lots of people with breast cancer,” says Harren.
“Novartis anticipates it will be one of their major cancer drugs in this area and they are looking at other tumour types too.”
A previous drug in the area, from Pfizer, was a multi-billion dollar product.
“Based on that, the analysts are predicting this will be a significant product for Novartis,” adds Harren.
Kisqali was developed using the fragment-based approach pioneered by Astex’s founders.
“Conventional small molecule drug discovery involved screening hundreds of thousands of compounds, which are around 400-500 molecular weight. This was the norm for most pharma companies in the mid-1990s when you had the ultra-high throughput screening mentality,” recalls Harren.
“There was a big belief that this was going to increase productivity in the search for new medicines. But it became quite apparent fairly quickly that there wasn’t generally the output for which we all hoped.
“We decided to take a radically different approach.
“Rather than screening compounds of that size, we decided to screen much smaller compounds – 100-150 molecular weight. That’s why these are described as fragments of larger drug molecules.
“If you keep the molecule smaller you have a much higher chance of having some initial interaction. The more complex or larger you make a compound, the more you lower the probability of fit with your target protein.”
The founders of Astex hypothesised that a library of 300 to 1,000 small fragments could explore chemical space more efficiently than a million-strong library of larger drug-like compounds.
“They can become seeds for growing a proper drug-size molecule,” says Harren.
“We wanted to see whether we could build a platform technology that would allow us to detect the binding of these small fragments to target proteins.
“One of the big challenges though is that if you have only one or two points of interaction between your fragment and your protein, the affinity is going to be extremely low.
“We needed a different way of detecting these hits.
“So the real development at Astex was to use biophysical techniques, particularly X-ray crystallography, to identify the binding of a fragment to the target protein.
“X-ray crystallography is a technique many use and one of the key advantages is that it provides the three-dimensional structure of a molecule.
“Not only can you identify fragment hits to the target protein, you can see exactly how they bind in the active site of the protein. That allows chemists to do some iterative rounds of chemistry to build the fragment up, improve the interactions with the protein and grow it into a drug-size molecule.”
Drug candidates developed using this approach are typically slightly smaller than compounds developed through standard methods.
“It’s a key point because if your drug molecules are much more than 500-600 molecular weight, they have a much higher failure rate in the clinic,” says Harren. “Larger molecules are not particularly well absorbed by cells and also give toxicity issues through off-target effects.”
Kisqali was developed after using X-ray crystallography to determine, for the first time, the three-dimensional structure of a protein called CDK4 that is involved in the initiation and progression of breast tumours. The drug works by inhibiting the protein.
“We used the crystal structure to refine the selectivity of the compounds,” says Harren. “The fragment approach gives you much better control over developing selectivity, as well as other physicochemical properties for a drug.”
Astex began with a focus on oncology as an independent, venture capital-based company, although it also developed partnerships in other areas – helping to progress an Alzheimer’s drug with AstraZeneca and Lilly, for example.
In 2011, Harren decided to merge Astex with Nasdaq-listed US pharmaceutical firm Supergen, which helped to take the new company – Astex Pharmaceuticals – public.
“They had a very strong development capability. Astex was really only a research-based company. They also had a strong balance sheet,” recalls Harren.
Then in October 2013, Astex Pharmaceuticals was acquired by Japanese-based Otsuka Pharmaceuticals in a deal worth $886million.
Since then, it has built a second therapeutic area in central nervous system diseases.
Today, Astex’s drugs pipeline is looking healthy.
It has a leukaemia drug undergoing phase III studies and others at an earlier stage that are designed to target advanced solid tumours and lymphomas.
In March, Astex was pleased to hear that erdafitinib, a drug developed with its pharmaceutical collaborator, Janssen Pharmaceutica NV, for the treatment of metastatic urothelial cancer, had been granted a priority review by the FDA in the United States.
The drug, developed using the fragment approach, inhibits fibroblast growth factor receptor (FGFr), which is implicated in tumour growth.
“It’s a great example of how biotech-academic collaborations can be so fruitful,” points out Harren. “This project started as a partnership between Astex and the Northern Institute for Cancer Research at Newcastle University.”
Astex is clearly on the up. It took over another unit opposite its existing Cambridge Science Park headquarters last year, taking its space from 35,000 sq ft to 75,000 sq ft and expanding its headcount to 130 people.
Sometimes, bigger is better.
Astex’s new microscope is the first of its kind
One of the newer and most exciting tools in the armoury of researchers trying to discover new drugs today is cryo-electron microscopy.
It enables scientists to determine the three-dimensional structure of molecules that could not be determined by conventional crystallography.
Astex has become the first company in the world to install a Thermo Scientific Glacios Cryo Transmission Electron Microscope (Cryo-TEM) as it seeks to find new therapies.
Harren says: “Cryo-electron micoscopy has really come on in leaps and bounds in the last few years. One of the requirements of X-ray crystallography is that you have to form crystals. With cryo-EM you don’t, which is a big advantage.”
Last year, Richard Henderson, at the MRC Laboratory of Molecular Biology (LMB) in Cambridge, shared the Nobel Prize in chemistry for his work in developing cryo-EM.
The microscopes are large, heavy and very expensive – they can cost several million pounds. But in Cambridge, a consortium brought together the LMB, pharmaceutical companies, the University of Cambridge and microscope manufacturer FEI – since acquired by Thermo Fisher Scientific – and it shares the cost burden so that scientists have access to the machines.
“This consortium came about from a conversation I had with Richard a few years ago when we were talking about how cryo-EM was developing and whether it would be useful for drug discovery one day. He was showing me some of the data,” says Harren.
“We figured one way was to establish a consortium and spread the risk. We approached other pharma companies, which joined, like AstraZeneca and Heptares. Together with the manufacturers, we put the consortium together. It’s still very early but I’m pretty confident it will have an impact on drug discovery.
“The consortium has two cryo-electron microscopes on the West campus. We have access to those and we’ve had one of our own installed at Astex. It’s the first of its kind.”
Astex’s Glacios Cryo-TEM is designed to have connectivity to the high-performance Thermo Scientific Krios Cryo-TEM system at Cambridge University. Scientists will be able to prescreen samples on the Glacios to find the best quality samples before advancing to the higher resolution imaging on the Krios Cryo-TEM.
Harren adds: “We are excited to be the first company in the world to have a new Glacios system installed in-house. We believe it will make an important contribution as we explore the potential of cryo-EM in our search for important new therapeutic agents.” Cryo-EM works by firing electrons through a very thin sample frozen in liquid ethane. The machine collects the 2D images from which a 3D shape is calculated. It boasts near-atomic resolution.
Mike Shafer, president of materials and structural analysis at Thermo Fisher, says: “The acceptance and adoption of Thermo Scientific cryo-EMs within the pharmaceutical industry has accelerated over the last year, and we are pleased the Glacios will be part of the vital research Astex is undertaking. The Glacios is a critical step in accelerating the workflow process for scientists researching pharmaceutical solutions for treating diseases.”
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