New approaches to drug discovery

Work from the University’s School of Life Sciences is having a major impact on commercial drug discovery programmes, shaping future drug development and driving billions of dollars in global investment.

Dundee-led research has pioneered new approaches to drug development, turning what were considered to be niche areas into dynamic fields of opportunity for pharmaceutical companies.

PROTACS

Research led by Professor Alessio Ciulli has underpinned the development of a new class of drugs known as PROTACS (proteolysis-targeting chimeras) that work with the cell’s natural processes, to target and degrade disease-causing proteins.

PROTACS work differently from traditional drugs. They have a particular mode of action that enables them to attack specific targets that were previously thought to be ‘undruggable’, offering a new technology that can be used across diverse diseases.

The approach offers a new line of attack for drug development programmes and has changed the way commercial drug discovery works, leading to large scale investment from global pharmaceutical companies, with PROTACS underpinning billions of US dollars in investment and the creation of a new spin-out company, Amphista Therapeutics.

Multiple companies cite the Dundee research in patents for new protein degrader drugs, and the first generation of PROTAC drugs have already entered clinical trials in humans, treating forms of prostate and breast cancer.

New partnerships have been formed with multiple pharmaceutical companies, driving further investment and generating income as new drugs are developed. Many of Ciulli’s PROTACS have been released through the Open Innovation portal ‘OpnMe’ making them freely available to researchers and driving further application in one of the fastest growing areas of drug discovery.

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LRRK2 and Parkinson’s Disease

Mutation of the LRRK2 gene is one of the causes of Parkinson’s disease – a debilitating and progressive disorder that affects 6 million people worldwide.

Work led by Professor Dario Alessi gave strong early indications about how the most common pathogenic mutation in LRRK2 might cause disease, by promoting LRRK2 hyper-activity. In turn, this indicated a potential treatment route through drugs that would inhibit the activities of LRRK2.

Alessi led the development of a synthetic substrate that allowed LRRK2 activity to be assessed, both by industry and academics, and this enabled the first screens for LRRK2 inhibitors by pharmaceutical companies.

After many years of work and in collaboration with others, he also uncovered the target substrates that LRRK2 acts on in cells and the relationship between mutations in LRRK2 and abnormal cell behaviours. In achieving these breakthroughs, Alessi identified biomarkers, and generated reagents to detect them, that have enabled clinical trials of LRRK2 inhibitors by allowing LRRK2 activity to be monitored in human blood cells.

Alessi’s evidence has provided a clear focus for global pharmaceutical companies, stimulating investments of over USD 1 billion in LRRK2 inhibitor therapies. His LRRK2-related reagents are used extensively by pharmaceutical companies and academia for preclinical research into Parkinson’s disease therapies.

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Exscientia

Exscientia is a spin-out company of the University of Dundee that is based on research of Professor Andrew Hopkins.

Declining drug discovery R&D productivity is a crucial challenge for the pharmaceutical industry, given that developing a new drug is estimated to cost USD 2.6 billion and take 10-15 years. Hopkins has been at the forefront of automating drug design by combining machine learning and big data analytics to harness chemical, pharmacological and biological data for better target identification and drug design. 

His spin-out, Exscientia Ltd, aims to use this approach to revolutionise productivity in drug discovery. Between 2014 and 2020, ExScientia attracted GBP 84million in investment, earned significant revenue and created 88 highly-skilled jobs. The company has over 18 partnerships with major global pharmaceutical companies and others.

Exscientia has reduced the cost and time taken in preclinical drug discovery. By the end of 2020, the company had delivered two novel drugs into first-in-human clinical trials, and was the fastest AI-design drug company to reach that critical stage.  

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