Research expertise at the ICT
Our research encompasses the development of new cancer medicines from concept to clinic. The emphasis of our work is on drug target and biomarker interrogation in clinical samples and development of relevant in vitro and in vivo models for lead compound selection and progression. Research covers the three broad stages of cancer medicine and biomarker development: discovery, pre-clinical evaluation and clinical application.
- We are one of a few centres nationally that has all the necessary research tools and expertise in-house to progress anticancer medicines and biomarkers from concept to the clinic
- The REF2014 assessment (Allied Health) placed 92% of the Institute’s research outputs in the 4* and 3* categories, and 100% of its impact and environment studies in the 4* and 3* categories
- Our research programmes include Phase I clinical trial support through partnership with St James’s University Hospital as well as other regional hospitals
The Medicinal Chemistry Team at the Institute is responsible for the design and synthesis of chemical compounds which are then evaluated for their biological activity and pharmacokinetic profile.
The team comprises a variety of expertise ranging from computer modelling to small and large scale synthesis. Our scientists use their expertise and the latest techniques to synthesise both individual as well as libraries of compounds for biological screening.
Our medicinal chemistry research is supported by post-doctoral research assistants, PhD students, MSc and MChem undergraduate project students. We annually welcome chemistry ERASMUS summer students from ESCOM and Sigma-Clermont (France) and the University of Turin (Italy), and frequently host undergraduate placements from other UK universities including York, Oxford, Leeds, and the University of Lisbon (Portugal).
We also offer our research expertise to industry details of which can be viewed here
Medicinal chemistry facilities
The YCR medicinal chemistry laboratories include facilities for the following:
- 20 fumehoods across two medicinal chemistry laboratories, as well as additional space comprising two preparation rooms, a walk-in cold room, a store room, write up area and offices
- Key equipment for synthetic chemistry, including dedicated LC-MS, polarimeter, UV spectrophotometer, analytical and preparative HPLC, automated peptide synthesiser
- Access to analytical instruments required for synthetic chemistry in the neighbouring Analytical Centre, including automated 400 MHz NMR for routine work and a 600 MHz NMR, facility for single crystal structure determination, mass spectrometers for low and high resolution mass determination as well as a ToF-MS, GC-MS, IR, Raman spectroscopy, etc
Drug target identification and characterisation
The aim of this research team is to address potential drug targets and assess their expression and/or activity in tumour tissue as opposed to normal tissue.
Once identified as potential targets further analyses are then undertaken to confirm that such targets are both clinically viable and have the potential for compound design and synthesis. In addition to the standard methods provided by our dedicated histology and immunohistochemistry facility, target interrogation may also utilise our flow cytometry, molecular pathology, confocal microscopy and real-time PCR (qRT-PCR) facilities.
The assessment of these potential drug targets as being clinically relevant is only made possible by the tumour bank resource established within the Institute.
Through our close partnership with UoB company Ethical Tissue Ltd we are able to source clinical tumour and normal tissue to evaluate potential drug targets.
The final stage of this phase in preclinical screening is the development of tumour cell models demonstrating differential levels of the purative drug target, either by identification of 'natural' expression levels or via genetic manipulation to create such models.
Drug screening and assessment of drug-target interactions
Once a target has been identified and compounds have been synthesised, the next phase is to identify 'hit' and 'lead' compounds by evaluating their potency against living tumour cells. In the tissue culture facility, we have access to in excess of 100 different human tumour cell lines representing different tumour types, drug responsiveness and drug target expression. Using these cell lines we screen compounds for their anticancer potency and efficacy. We also address the selectivity of the potential agents against their proposed tumour target and establish their mechanisms of action.
Drug toxicity, drug target selectivity and anti-tumour efficacy
When a 'lead' compound has been identified by extensive in vitro assessment, we then evaluate whether there is any drug toxicity, sufficient bioavailability, interaction of drug with target and efficacy in well-characterised, relevant tumour models.
DMPK and clinical pharmacology
The Institute has an experienced Drug Metabolism and Pharmacokinetic (DMPK) team with an efficient and well resourced analytical set-up.
The DMPK team plays a central role in the drug discovery process within the ICT and works closely with other members of the Institute in studies both at preclinical and clinical stages. ADME, tissue distribution, and studies with recombinant enzymes are routinely undertaken. Previous studies have included the analysis of complex metabolic profiles and the development of analytical methods for the PK analysis of highly reactive and potent molecules in the picomolar range.
Recent experience has also shown us that the sensitivity afforded by LC/MS/MS is essential to monitor low concentrations of highly potent metabolites or pharmacodynamic markers in small (low mg) clinical biopsy samples as we have successfully achieved in a recent Phase I clinical trial. We also assist lead compound optimisation by developing in silico models to predict the dynamics of drug exposure of solid tumours using tissue penetration and plasma pharmacokinetic data obtained from lead compound investigations.
The GCLP facility is supported by a Quality Control Manager and is central to the laboratory support of clinical trials.