The discovery of therapeutics for neglected diseases and the translation of novel biology through small molecule drug discovery

Research

Head of the Drug Discovery Unit

The Drug Discovery Unit (DDU) (est. 2006, see http://www.drugdiscovery.dundee.ac.uk) within the College of Life Sciences at Dundee was created to respond to a lack of capacity in the UK for early stage drug discovery in the academic sector. The DDU’s aim is to translate basic science into lead compounds to validate putative drug targets, to use as tools to investigate disease pathways and, when appropriate, advance to pre-clinical drug candidates. The DDU works to Biotech style philosophy and standards incorporating; dynamic, goal driven project management based on Target Product Profiles and Compound Selection Criteria. The DDU is the only fully operational and integrated drug discovery team within UK universities with the full range of disciplines including compound management, screening, molecular pharmacology/enzymology, medicinal chemistry, computational chemistry, DMPK and disease model capabilities, required to produce novel hit and lead candidates.

The DDU seeks to work in collaboration with groups with novel biology to translate the ideas into early stage drug discovery. Within the collaboration the DDU seeks to identify high quality compounds i) to enable the target originating group to develop their understanding of the biology and to partially validate the potential drug target and ii) use them as start points for drug discovery programmes.

As Head of the Unit I have overall responsibility for the direction, strategy and the scientific quality of the output of the Unit.

Drug Discovery for Tropical Diseases

The Drug Discovery for Tropical Diseases Initiative is a programme to discover high quality drug candidates for African sleeping sickness. The initiative is funded by the Wellcome Trust, with a budget of £8.1m over five years. My role as Director of Drug Discovery is to lead a high quality multi-disciplinary drug discovery team; to integrate in house resources and external collaborations to rapidly identify hit series and progress them through to pre-clinical candidates; control budgets and seek additional funding when required; lead out-licensing discussions with potential clinical development partners; build contacts and collaborations with other groups.

In addition, we are funded by Drugs for Neglected Diseases initiative (DNDi), with a budget of £1.8m over 5 years, to identify lead optimisation opportunities for Leishmaniasis.

My background is in medicinal chemistry, with a broad experience of drug discovery in both large Pharma and Biotech, especially through leading a project from hit identification through to regulatory applications for starting clinical trials. One compound from the project is currently undergoing Phase II clinical trials in cancer patients and a second compound spun-out of the project is also in Phase II clinical development.

My particular area of interest is in the use of structural information such as X-ray structures of target-inhibitor complexes or compound based pharmacophore models to design drug candidates. Although, computational chemistry is invaluable in designing compounds with improved activity, the most potent compounds do not necessarily make the best drugs. Therefore within the group we use computational methods to design in good pharmacokinetic properties as well as potent activity to deliver quality drug candidates.

Teaching

Publications

1. Frearson, J.A. et al (2010) N-Myristoyltransferase inhibitors: new leads for the treatment of African sleeping sickness. Nature, 464, 728-732. [PMID: ://www.ncbi.nlm.nih.gov/pubmed/20360736].

2. Spinks, D. et al (2009) Investigation of trypanothione reductase as a drug target in Trypanosoma brucei. ChemMedChem, 4: 2060-2069.

3. Torrie, L.S. et al (2009) Chemical validation of trypanothione synthetase: a potential drug target for human trypanosomiasis. Journal of Biological Chemistry, 284, 36137-36145.

4. Mpamhanga, C.P. et al (2009) One scaffold, three binding modes: novel and selective pteridine reductase 1 inhibitors derived from 2 fragment hits discovered by virtual screening. J. Med. Chem. 52, 4454-65

5. Frearson, J. A. et al (2007) Target Assessment for Anti-Parasitic Drug Discovery. Trends in Parasitology, 23, 589-595 

6. Brenk, R. et al. (2008) Lessons learnt from assembling screening libraries for neglected disease. ChemMedChem. 3, 435-44. 

7. Wyatt, P. G. et al. (2008) Identification of N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design. J. Med. Chem. 51(16), 4986-4999.