Page 14 - The Keble Review 2016

14
The Keble Review 2016
Drug Discovery
ina Public-Private Partnership
Oakley Cox tDPhil Candidate
he pharmaceutical industry (or pharma) has been hugely successful in discovering new medicines. Treatments
for diseases which place a significant burden on society,
such as diabetes and cancer, continue to improve. However, the development of blockbuster drugs has been slowing in recent years owing to the rising cost of bringing a drug to market, alongside expensive late stage failures. As a result, many pharma companies have closed research and development sites around the globe, and have been forced to restructure with the loss of thousands of jobs.
Until recently, the role of academic research in pharma drug discovery programmes was limited. Results published by universities in scientific journals were considered at best irrelevant, at worst unreliable. A landmark publication by C Glenn Begley and Lee M Ellis published in the journal Nature in 2012 shed light on the scale of the problem; the authors’ attempts to reproduce the findings of high impact cancer research showed only an 11% success rate.
Collaboration between leading researchers in industry and my department, the Structural Genomics Consortium (SGC, www.thesgc.org), is bidding to bring academia and pharma closer together. Founded in 2004, the SGC is a public-private funded research community with centres at the University of Oxford and the University of Toronto, Canada. By applying academic
and industrial expertise to biomedical problems, the biological mechanisms which cause disease can be better understood and new therapeutic targets found. The consortium has had success with a large number of high impact publications and the discovery of numerous drug-like molecules. One drug candidate, JQ-1, is currently undergoing clinical trials as a male contraceptive whilst other molecules have been released as a part of the SGC Chemical Probe Project. These chemical tools have proved incredibly successful in unearthing new biological insight thanks not only
to their relevance to pharma drug discovery projects, but also pharma’s ability to reproduce the results in their own labs.
Collaboration between Diamond Light Source (DLS) and the SGC has recently made further strides in the discovery of novel drug- like molecules. DLS is a publicly funded facility near Didcot which uses a high-speed electron beam (a synchrotron) as a source of high energy X-rays. When the X-rays are focused at the crystals of purified protein, a 3D structural image of the protein can be created. The technique, known as protein X-ray crystallography, can be used to obtain highly detailed images of proteins interacting with drug-like molecules. The ability to understand
how the drug-like molecule is inhibiting the protein’s function at the structural level is invaluable to further molecule development and future drug discovery. Traditionally, the process has been labour intensive and time consuming, but drug discovery using X-ray crystallography at DLS is now a viable technique thanks to the introduction of robotics and automated data collection.
My research has centred on demonstrating the utility of
the new facility at DLS. I began by building a library of
small molecules for screening against proteins using X-ray crystallography. The molecules were selected by virtue of containing one or more chemically poised bonds, making each one amenable to synthesis using standard organic chemistry reactions. As a result, a series of similar molecules can be readily synthesised when a molecule is identified binding to a protein. The library was then screened against previously untargeted epigenetic proteins – the proteins which regulate the expression of DNA in human cells and are widely linked to cancers and autoimmune diseases. A number of them were found to bind and when follow-up molecules were synthesised, they were found to inhibit the proteins’ biological functions.
As a result of my research and others at DLS and the SGC, it is hoped the new protein X-ray crystallography facility will offer a major breakthrough in industrial and academic drug discovery.
By pooling resources with organisations like the SGC and DLS, industry researchers are hoping to get a better understanding of fundamental biology and have access to a world-leading facility at a fraction of the cost it would take to build the infrastructure in-house. DLS also aims to reinvigorate high quality drug discovery within universities by giving academic researchers access to the kinds of technology previously only accessible to a handful of pharma companies. It is hoped the increase in relevant and reproducible research will bring a timely boost to an industry striving to tackle the next major disease areas such as Alzheimer’s and antibiotic resistance.
Oakley matriculated at Keble College in 2008 to read Chemistry.
He completed his Masters in 2012 and was offered a place at the Oxford Doctoral Training Centre. His course, Systems Approaches to Biomedical Sciences, uses expertise from the physical sciences to tackle biological problems. During his DPhil, Oakley has designed a library of molecules for drug discovery using protein X-ray crystallography under the supervision of Professor Paul Brennan at SGC Oxford and Professor Frank von Delft at Diamond Light Source, Didcot.