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Research by the School of Pharmacy has underpinned the development of fluorescent ligand probes that have opened-up new pathways in drug discovery. These ligands have been commercialised through the formation of the spin-out company CellAura Technologies Ltd, and have been made globally available through a number of distributer agreements. Customers include pharmaceutical companies (e.g. Pfizer, AstraZeneca), drug discovery biotechs (e.g. Addex, Heptares) and drug discovery technology providers (e.g. CisBio). These ligands provide alternatives to the use of radio-ligands, giving more informative and safer solutions for industrial drug discovery. This has, for example, enabled: a new direction in G protein-coupled receptor research at Novartis Pharmaceuticals UK Ltd; validation of Promega Corporation's new drug-binding assay; and superior performance in the establishment of cell lines at inSCREENex GmbH.
Fluorescent ligand technologies developed by Professor Hill and Dr Briddon in the Pharmacology research group, in collaboration with Professor Kellam in the School of Pharmacy, permitted biophysical analysis of G-protein coupled receptors (GPCRs) at the individual cell and molecule level for the first time. The technologies have been commercialised through the spin-out business, CellAura Technologies (and their distributors Abcam, Sigma-Aldrich and others), generating revenues and making the products available to researchers and drug discovery communities worldwide. Custom product developments with global pharmaceutical companies and drug screening reagent providers have generated further partnership revenues and technology benefits. Nottingham-trained researchers are now employed worldwide, broadening the technology's impacts.
Research conducted at the University of Bristol since the late 1990s has pioneered the development of over 60 chemical probes that are selective for individual ionotropic and metabotropic glutamate receptors. The development of these probes has led to numerous commercial impacts, including: the establishment of two companies, which both sold during the assessment period for a combined value of £85 million, and sales revenue for global providers of biochemicals. This research has also stimulated considerable industry investment in drug development.
Professor Geoffrey Burnstock and colleagues' establishment of the molecular structure of the P2Y class of receptor led to the cloning of several receptors within this class, which are increasingly seen as therapeutic targets for a variety of disorders. Indeed, drugs acting at these receptors are already improving patient health worldwide by reducing the risk of thrombotic events in people suffering from myocardial infarction or ischaemic stroke (via P2Y12 receptor antagonists) and by relieving the symptoms of dry eye disorder (via P2Y2 receptor agonists). Burnstock and colleagues also cloned the P2X3 receptor which mediates pain information, and P2X3 antagonists are being developed as novel analgesics. As well as clear clinical benefits, these drug developments are associated with substantial economic and commercial benefits.
Research by Professor Kevin Fone in the Neuroscience group has established and characterised rodent models of CNS disorders that have been instrumental in validating several 5-hydroxytryptamine (5-HT) receptors as therapeutic drug targets to treat learning and memory dysfunction in humans. Specifically, animal studies to validate the 5-HT6 receptor for cognitive impairment in Alzheimer's disease (AD), depression and schizophrenia have resulted in R&D investment in drug discovery programmes by several global pharmaceutical companies. Consequent advances in healthcare benefits (current and potential) are also summarised.
Research led by Dr. Peter Richardson in the Department of Pharmacology led to the development of an A2A adenosine receptor antagonist (istradefylline) for the treatment of Parkinson's disease. In 2001, Dr Richardson founded the spin-out company Cambridge Biotechnology (CBT) to develop these drugs. A pH-sensitive adenosine A2A receptor agonist is now being developed for the treatment of neuropathic pain, with one product licensed for use in Japan in 2013 (Nouriast). Small-molecule leptin mimetics as potential anti-obesity drugs were also developed, initially by CBT and since 2009 by Astra Zeneca following acquisition of the research programme. CBT has undergone a number of high-value acquisitions, by Biovitrium, Proximagen, and most recently Upsher-Smith. It continues to operate as a wholly-owned subsidiary, employing 30-35 people from 2001 to the present.
Members of the Pharmacology Research Group identified hitherto unknown properties of G protein Coupled Receptors (GPCRs): that ligands can signal differentially through both G-protein-coupled and β-arrestin pathways. This led to the concept of GPCR `biased signalling' and development of fluorescent reporters to quantify β-arrestin signalling. These discoveries have been adopted widely by the pharmaceutical industry, attracting R&D investment and collaborative research funding, to drive discovery of new drugs operating through `biased signalling'. The commercial opportunity has also been exploited by screening reagent providers and contract screening organisations. These discoveries will ultimately produce better drugs to treat GPCR-based diseases to improve human health.
The Farndale group have identified fragments of collagen, synthesised and assembled in active, triple-helical conformation, for use as ligands to manipulate platelet function. As a result of this work, the fragment Collagen-Related Peptide (CRP) is included in British Committee for Standards in Haematology guidelines as a platelet agonist for the diagnosis of platelet defects. The group has also synthesised triple-helical collagen peptide libraries and used them to map binding of cells or proteins to collagen more widely. The peptides are made and distributed by the Farndale lab, generating income through sales and licencing, and are used internationally by companies and hospitals to develop diagnostics and for high-throughput drug discovery. Prof Farndale also acts as a consultant for companies developing diagnostics.
A new anti-inflammatory molecule FX125L was developed by David Fox at Warwick, in collaboration with David Grainger (Department of Medicine, Cambridge) and Funxional Therapeutics Ltd (FXT). Research in lead optimization, mechanistic preclinical chemistry, synthetic route development (for scale-up), and CMC (chemistry, manufacturing and controls) was conducted at Warwick. As a result FX125L completed Phase 1 and entered Phase 2 clinical trials in humans for the treatment of asthma or other inflammatory diseases. Its sale to Boehringer Ingelheim generated a multi-million pound return for FXT and its investors.
Imperial College preclinical studies guided the desired selectivity profile for long-acting muscarinic receptor antagonists (LAMA). Binding, functional and clinical studies from Imperial laboratories were the first to demonstrate the long duration of tiotropium bromide (Spiriva®) in human tissue, and confirmed its long duration of action in patients and established it as the first-line treatment for chronic obstructive pulmonary disease (COPD). Tiotropium has had a beneficial impact on the management of COPD and is incorporated into the major international treatment guidelines. It improves symptoms, reduces exacerbations and mortality, and provides a cost-effective therapy. Imperial have also produced the first pre-clinical and clinical data for the next LAMA in development (glycopyrrolate, Seebri®), which has recently been marketed. Our profiling of tiotropium has also led to the development of several novel LAMA.