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Astex Pharmaceuticals – Structural Biology Revolutionises Drug Discovery

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Astex Pharmaceuticals – Structural Biology Revolutionises Drug Discovery Astex Pharmaceuticals – structural biology revolutionises drug discovery n 1999, Professors Tom Blundell and Chris Abell from the University of Cambridge, and Dr Harren Jhoti formerly head of structural biology and bioinformatics at pharmaceutical company GlaxoWellcome IMPACT SUMMARY I(now GSK) founded Astex Technology to commercialise a new approach to drug discovery. The company, which changed its name to Astex Pharmaceuticals in 2011 when it merged with SuperGen Inc.1, was sold for Astex Technology was founded in 1999 to $886M in 2013 to Otsuka Pharmaceutical Co. Ltd2. commercialise a new approach to small molecule drug discovery, called fragment Their ‘structure-guided fragment-based’ approach, Head of Worldwide Discovery at Pfizer and a former member based drug discovery now used by major developed by Blundell and colleagues from decades of of the Astex Scientific Advisory Board. pharmaceutical and biotechnology companies. structural biology research, is now employed by many In 2011, Astex merged with SuperGen major pharmaceutical companies, including GSK, Novartis, “Astex Pharmaceuticals was listed on NASDAQ (ASTX) and is Inc. for $150M and was re-named Astex AstraZeneca and Johnson and Johnson, alongside their one of the most successful British biotechnology companies Pharmaceuticals. In September 2013 Astex traditional drug discovery programmes. ever,” explains Dr Roberto Solari, former Vice President in Pharmaceuticals was acquired by Otsuka the Respiratory Therapy Area at GSK, and former Astex Pharmaceutical Co., Ltd. for $886M. Astex has used the approach to develop four potential drug employee. Astex has received approximately £65M in compounds in-house, which are all now in clinical trials, and funding from pharmaceutical companies such has worked with industry partners to develop several others. Much of the structure-guided research that led to as GSK, AstraZeneca, Novartis and Johnson “It is truly remarkable that Astex pioneered and validated the creation of Astex was funded by one of BBSRC’s & Johnson. GSK and AstraZeneca have now their fragment-based approach to drug discovery so quickly predecessors, the Science and Engineering Research Council established their own fragment-based discovery and successfully, and that it has had such a profound and (SERC), while BBSRC continued to provide support for the capability. productive impact technically and clinically throughout the later structural biology work. pharma and biotech sector,” Dr Simon Campbell, former Since 2003 Astex has employed between 80 and 100 people. Former Astex employees now occupy senior positions at UCB, Heptares and Evotec, amongst others. Astex is developing four potential new cancer drugs in-house. They are all in phase I or phase II clinical trials. Drugs arising from Astex’s drug discovery collaborations with its partners Janssen, Novartis, and AstraZeneca are currently in clinical trials from Phase 1 to Phase 3. Hodgkin’s wire model of the structure of insulin. Image: User:sc63/Flickr/CC BY-NC-SA 2.0. 1 Astex Pharmaceuticals – structural biology revolutionises drug discovery Fragment-based discovery cancers, such as gastrointestinal stromal tumours, mantle In 2011, Astex merged with SuperGen Inc. for $150M and Blundell, Abell and Jhoti founded Astex Technology Ltd in cell lymphoma, chronic lymphocytic leukemia and multiple the new company was re-named Astex Pharmaceuticals. In 1999 to pioneer the development of a new approach to myeloma. Several of Astex’s collaborators also have drugs September 2013 Astex Pharmaceuticals was acquired by drug discovery. Funding from venture capitalist investors in clinical trials5: Janssen Research and Development are Otsuka Pharmaceutical Co. Ltd. for $886M. Abingworth Ventures enabled them to demonstrate in 2000 developing a drug to tackle solid tumours of lymphoma, The structure-guided approach that they could detect the position and orientation of small Novartis are targeting malignant rhabdoid tumours and Many of the advances in X-ray crystallography that made molecule ‘fragments’ bound to target proteins at high neuroblastoma, and AstraZeneca are developing drugs for structure-guided drug discovery possible occurred between resolution using X-ray crystallography3. These fragments prostate cancer and Alzheimer’s. the 1920s and 1950s. In particular, Professor Dorothy could then be modified to create novel drug precursors. Hodgkin at the University of Oxford carried out much of Since 2003, the company has employed between 80 the earliest work to characterise biomolecules using X-ray The results were published in 2002 and attracted the and 100 people on the Cambridge Science Park, and has techniques. attention of several major pharmaceutical companies. Astex continued to receive significant investment. Over the past subsequently received funding from, and collaborated with, decade Astex has received collaborative funding from As the technology advanced, researchers began to tackle GSK, AstraZeneca, Novartis and Johnson & Johnson. “Astex Pharma (GSK, AstraZeneca, Janssen and Novartis) of larger, more complex biological molecules. In 1969 Hodgkin, scientists rapidly established a world class reputation for approximately £65M in addition to approximately £80M who led much of the work on applying X-ray crystallography innovation and scientific excellence as they consistently raised from a number of venture capital investors6. to such molecules, mapped the structure of the hormone demonstrated that very small molecules could be insulin after more than three decades of work7. Blundell’s transformed into clinical candidates more efficiently than research into protein structure began in the 1960s, working traditional approaches,” says Campbell. “As a consequence with Hodgkin, where he was interested in the development of Astex success, fragment-based approaches are of new, longer-lasting insulins8 for treating diabetes, based commonplace throughout pharma and biotech.” on an analysis of the activity of insulin9. Much of this work was undertaken in collaboration with Helmut Zahn at RWTH GSK and AstraZeneca subsequently established their Aachen University in Germany, Panayotis Katsoyannis at the own fragment-based discovery capability. Former Astex University of Pittsburg in the US, and others. employees and members of Blundell’s research group at Cambridge have also worked at companies including UCB In parallel with developments in X-ray crystallography, in (Rich Taylor, driving fragment-based discovery at UCB the 1970s several different computer graphics systems Slough), Heptares (Miles Congreve, applying fragment- were created which enabled researchers to construct and base discovery to G protein-coupled receptors at Heptares) manipulate computer models of complex molecules such and Evotec, all of which have established fragment-based as proteins10. Previously, the only way to do so had been programmes. through elaborate physical models. The structure-guided fragment-based approach has led Together, these new technologies paved the way for the to the creation of several potential new drugs. Astex is structure-guided approach developed by Blundell, Abell and developing four potential drug molecules though their own Jhoti and commercialised through Astex. in-house programmes, all of which are in phase I or phase II Astex is developing new cancer treatments. Image: Shutterstock. clinical trials4. They include treatments for several different 2 Astex Pharmaceuticals – structural biology revolutionises drug discovery Proof of principle They published the structure Building on his earlier work with Hodgkin, Blundell jointly with Pfizer scientists in demonstrated the structure-guided approach to drug 1989 and used this information discovery in the late 1970s and early 1980s, with support to begin to design anti-retroviral from SERC and in collaboration with companies such as drugs to help combat AIDS15. ICI, the Wellcome Foundation and Pfizer. At the time, Blundell was interested in the structure of enzymes that cut Following this, Blundell worked proteins. These included renin, which plays an important with pharmaceutical companies role in regulating blood pressure and is important for including Pfizer, Parke Davis, MSD, cardiovascular health. In 1983, Blundell published a paper and Zeneca to apply the structure- in Nature describing a computer model of the three guided approach to optimise dimensional structure of renin11. X-ray crystallographic potential drug compounds and studies followed in the late 1980s and early 1990s12. develop new drug candidates. He also received funding from Renin plays a role in raising blood pressure by cutting a BBSRC to continue to develop protein, angiotensinogen, to create angiotensin I, which is his research into protein in turn converted into angiotensin II. Angiotensin II causes structure through the ‘Molecular blood vessels to contract, forcing the heart to work harder to Recognition’ initiative and a ROPA 3D ribbon model of the protein renin. Image: Wikimedia Commons. pump blood and so increasing blood pressure. (Realising Our Potential Award) grant16. The information from the X-ray crystallography studies Chris Abell, Professor of Biological Chemistry at Cambridge, combined with computer modelling enabled Blundell and Harren Jhoti, who was formerly head of structural biology colleagues to design a compound, using their structure- Astex scientists rapidly and bioinformatics at GlaxoWellcome (now GSK), and guided approach, which bound to renin and prevented it established
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