It has become increasingly clear that rather than being a single disease, cancer is a heterogeneous collection of diseases.
In order to diagnose and treat cancer effectively, strategies for patient selection must be combined with the development of molecularly targeted therapeutics so that patients can receive the drug or combination of drugs which is most appropriate for the treatment of their disease, at the appropriate time.
This approach necessitates the involvement of multi-disciplinary teams of basic researchers and clinicians, working within an infrastructure which allows for effective knowledge transfer.
Drug Discovery Group
Professor Tim Harrison (Lead Investigator)
The Drug Discovery Group at the Centre for Cancer Research and Cell Biology (CCRCB) integrates both academic and industrial scientists as part of a strategic collaboration between Queen’s University Belfast and Almac Discovery, to facilitate the translation of basic research discoveries into products which can ultimately derive value for patients.
Working in close partnership with researchers from across the University and local hospitals, as well as with external researchers, the mission of the Drug Discovery group is to identify molecular targets which are relevant to disease and to develop strategies to modulate their function. Working closely with colleagues within the Centre (which includes the Northern Ireland Molecular Pathology Laboratory and Northern Ireland Biobank), a strong emphasis will be placed on the early development of biomarkers, both to aid patient selection, and to establish that the drug is interacting with its intended target in patients.
Key to the progression of any drug discovery programme is the identification of a chemical compound (either small molecule or peptide/protein based) which can interact with the target. This drug “hit” is then optimised to provide a compound (often termed a Preclinical Candidate) which has the potency, specificity and pharmaceutical properties to interact with the target in humans at a therapeutic concentration which does not cause unacceptable side effects. This candidate molecule is further evaluated in pre-clinical development studies before progressing into clinical trials.
The capabilities of the Drug Discovery group include:
- Medicinal chemistry expertise in hit identification, hit to lead and lead optimisation;
- Biology expertise in target validation and assay development using multiple formats;
- Fragment screening (using a range of orthogonal biophysical techniques);
- Computer aided drug design and chemoinformatics;
- Bioinformatic expertise in data mining;
- Measurement and interpretation of Absorption, Distribution, Metabolism and Excretion (ADME) and physicochemical properties of molecules;
- State of the art compound storage and data management facilities;
- Pre-clinical and clinical project management;
- International network of collaborators and outsourced service providers.
Academic Medicinal Chemistry Group
Our lab is an academic medicinal chemistry group focused on the development of small molecule protease inhibitors that are relevant in human diseases, such as cancer and Cystic Fibrosis.
Working with experts in the field of both protease chemical biology and cancer biology we have developed a number of small molecule inhibitor programmes, such as the Legumain project with Dr Paul Mullan.
We are also involved in the CRUK accelerator programme in structural biology with Professor Richard Bayliss (Leeds). This programme allows us to put forward nascent drug discovery projects from Queen’s University that would be enhanced significantly by access to fragment screening (Beatson), protein production (Newcastle, Leicester), computational chemistry (ICR) and x-ray crystallography (Leeds, Leicester).
In addition, through interactions with Professor Harrison and the Almac Discovery group we have been able to drive the identification and development of a significant number of molecular starting points for further exploration.
Further information on our programmes is available below.
Current Research Programmes in the Academic Medicinal Chemistry Group
Legumain Inhibitor Programme (with Dr Paul Mullan)
Research carried out in the lab of Dr Paul Mullan identified Legumain, a cysteine protease from the C13 clan, as a marker of poor prognosis in breast cancer (D’Costa, Z., et al, Oncotarget, 2014, 5, 1609). Further research has revealed similar findings in a number of other human cancers, such as ovarian, pancreatic and prostate cancer. Interestingly, depletion or suppression of Legumain has shown that these cancers have a significant addiction to this protease. Unlike in the cancer setting similar experiments with normal cell lines have revealed no impact upon cell viability suggesting that Legumain could be a powerful anti-cancer target that will spare human toxicity which is observed with current treatment options.
Using multiple starting points for hit finding, we have now identified potent, selective and cellular active inhibitors of Legumain with improved physiochemical properties (Higgins, C.A., et al., Bioorg. Med, Chem. Lett., 2014, 24, 2521; Ness, K.A., et al., Bioorg. Med, Chem. Lett., 2015, 25, 5642; Ness, K.A., et al., Bioorg. Med, Chem. Lett., 2015, 25, online asap). The lead compound from this research is currently being scaled up for in-vivo testing in early 2016. We have also provided tool compounds from this project to research groups across the globe.
Cathepsin S Inhibitor Programme with Professors Scott (School of Pharmacy), Taggart and Elborn (Centre for Infection and Immunity)
Cystic fibrosis (CF) is an autosomal recessive disorder that is caused by mutations in both copies of the CFTR gene (Cystic Fibrosis Transmembrane conductance Regulator). CFTR is known to be involved in the secretion of bodily fluids, such as sweat and mucus. CF can affect a number of organs in the human body including the pancreas, liver, intestine and kidneys, but is mostly commonly associated within the lung. Loss of CFTR in the lung is associated a thickening of mucus and a decrease in lung function over time. Patients suffering from CF have difficulty in clearing mucus which provides an ideal bed for infections. Recent numbers published by Cysticfibrosis.org show that there are currently over 10,000 people suffering with CF in the UK alone.
Through our collaborative research into CF, we have discovered that Cathepsin S (CatS), a potent elastolytic enzyme, plays a major role in the progression of the disease in the lung. We have observed, through a number of studies using small molecule inhibitors of CatS an impact on multiple hallmarks of CF confirming CatS as a bona fide drug target.
We have initiated a drug development program around the identification of a small molecule CatS inhibitor that can be delivered directly to the lung. The design features of this class of compound are somewhat different to either oral or IV drugs. To aid this program through to pre-clinical development we have been working with experts in the field, such as Dr John Dixon (former head of research at AZ) and scientists in Argenta.
Cathepsin S in Cancer (with Professor Chris Scott and Dr Roberta Burden)
Recent studies have interrogated the impact of CatS with regards to the tumour microenvironment. We have identified that tumour-derived and microenvironment-derived CatS both have significant roles to play in facilitating tumour growth, through proliferation, apoptosis and angiogenesis (Small, D., et al, Int J Cancer, 2013, 133, 2102). Furthermore, the importance of macrophage-derived CatS has also been examined, with studies demonstrating its contribution in murine tumour model growth and more recently in mediating breast-to-brain metastasis (Gocheva, V., et al, 2010, 24, 241; Sevenich, L., et al, 2014, 16, 876).
Extensive work has been carried out to identify protease substrates in order to elucidate protease-specific roles within biological processes. We have ascertained that CatS can regulate the expression of several pro-tumourigenic factors, most notably the pro-inflammatory chemokine, CCL2. We showed that this regulation appears to occur through CatS cleavage of CD74, which in turn transcriptionally regulates CCL2 expression, through the activation of NFkB. Interrogation of patient microarray datasets has confirmed the clinical correlation between CatS and CCL2, highlighting physiological significance and strongly suggests that CCL2 may be a potential biomarker of CatS activity within disease (Wilkinson, R.D.A, et al., Oncotarget, 2015, 6, 29725).