This Science Hot Topic is based on a between-issue updates article by Isaac Bruce for Chemistry Review Magazine. Subscribe to Chemistry Review now – from just £40.

Not content with providing more Olympic medallists than most countries, a few years ago Yorkshire was in the news again thanks to the discovery and development of a new anti-cancer drug: olaparib.

Discovering Olaparib

Helen Bryant is the lead author of the paper documenting the discovery of olaparib. She studied medical biochemistry and became head of the DNA replication and repair group at the University of Sheffield. Helen extols the power of laboratory research: ‘It shows what funding novel laboratory ideas at the grass roots level can do to change the treatment options available to patients.’

PARP Inhibitors

Olaparib is the first of a group of drugs called PARP inhibitors. PARP is the enzyme poly ADP ribose polymerase (ADP is adenosine disphosphate), which is responsible for repairing damage to DNA (deoxyribonucleic acid).

During replication DNA can encounter ‘nicks’ in the single strands. If left unrepaired, these nicks can lead to double-strand breaks and ultimately the death of the cell.

Normal, healthy cells can use a secondary mechanism to repair the break if the PARP mechanism fails, but cancer cells with a BRCA (breast cancer early onset gene) mutation cannot. Thus, olaparib targets the cancerous cells by preventing DNA repair.

BRCA mutations are often hereditary and leave women at a predisposition to ovarian and breast cancers. Following successful clinical trials, olaparib is now approved by the United States Food and Drug Administration (USFDA) and the European Medicines Agency (EMA). A panel from the National Institute for Health and Core Excellence (NICE) is still to decide if it can be used in UK hospitals.

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TNF Inhibitors

Andreas, a 48-year-old Spanish man, has a chronic inflammatory disease called ankylosing spondylitis, which affects his spine. This disease causes levels of pain you might not believe possible, rendering the sufferer stiff and unable to move. If left untreated it leads to new bone formation in the spine, causing the back to end up in the shape of a question mark. The only prognosis for the patient is life confined to a wheelchair — or at least it was.

20 years ago, when Andreas was diagnosed with this disease, he slept in an upright position, he hardly ever left his house and he became fed up with life.

Treating this disease is complicated. Often patients start on NSAIDs (non-steroidal anti-inflammatory drugs) or traditional DMARDs (disease-modifying anti-rheumatic drugs), where the mode of action is not clear. These are ‘old’ drugs, where the investigations into their use have demonstrated that they work, but it is not clear how. Often there is an initial positive response, but the pain and the disease will come back.

When treating ankylosing spondylitis and other chronic inflammatory conditions, it is important to understand what controls the disease. Targeted therapy (investigating how a disease works, selecting a specific protein that you know controls the disease and then creating a therapy to specifically target it) is the best way of controlling the patient’s condition.

In this case, the class of therapy was the TNF (tumour necrosis factor) inhibitors. TNF is an important cytokine protein on the inflammatory cascade and controls cell death, among other functions. The protein also promotes the production of other inflammatory proteins, leading to further inflammation and pain for the patient. Along the inflammatory cascade are other cytokines that control the disease — these are all potential targets and many small-molecule compounds are currently in development that target other proteins, such as JAK1/2 and IL-17.

For 10 years Andreas was administered NSAIDs and for those 10 years he lived a life of pain. Once he started therapy on a TNF inhibitor, it changed his life. Within 2 weeks he had noticed a significant difference to his quality of life and now, 10 years later, he has completed two ultra-open water swims, one in world record time. This disease usually confines patients to a wheelchair, but this targeted therapy, discovered and developed by people working in academic and industry institutions, has dramatically changed the lives of Andreas and millions of others.

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