Our approach to research excellence
The Institute of Cancer Therapeutics is world-renowned for research, training and partnership with industry. Our excellence is testified by substantial investment from industry and research councils, leading to high impact outputs, innovation and knowledge transfer.
The REF 2021 assessment placed over 80% of outputs in Allied Health Professions rated as Internationally Excellent or World Leading (3* or 4*).
Research Excellence Framework Assessment 2021
Medicinal Chemistry
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).
Medicinal chemistry facilities and expertise
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
Expertise
We have expertise in a range of areas including:
- Parallel and library synthesis
- Improving pharmaceutical properties
- Computer aided drug design
- Scale up
- Stable isotope labelling
- Multiple step synthesis
- Lead optimisation
- Structure identification
Drug target identification and characterisation
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 University of Bradford partner Ethical Tissue 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 GCP facility is supported by a Quality Control Manager and is central to the laboratory support of clinical trials.
DMPK Expertise
ICT has an experienced Drug Metabolism and Pharmacokinetic (DMPK) Team, led by Prof Paul Loadman, who have worked on numerous contract research projects with industrial partners within efficient and well-resourced GCP laboratories. The team undertake analytical method development (LC-MS/MS) and a range of bioavailability and pharmacokinetic studies from simple evaluation of parent molecule in plasma to full ADME and tissue distribution.
Advantages of working with the DMPK team at ICT:
- Excellent knowledge and experience in this area- expert opinion from leading academics
- GCP accredited laboratories and high quality research and reporting
- Projects are managed to meet commercial timelines and we ensure our partners are fully updated on progress
- Examples of studies include 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.
We have also successfully monitored low concentrations of highly potent metabolites and pharmacodynamic markers in small clinical biopsy samples as in a recent Phase I clinical trial.