University of Dundee

Professor Paul Wyatt FRSE

The discovery of therapeutics for neglected diseases and the translation of novel biology through small molecule drug discovery
Position: 
Professor of Drug Discovery and Head of the Drug Discovery Unit
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 386231, int ext 86231
Email: 

Research

Head of the Drug Discovery Unit

The Drug Discovery Unit (DDU) (est. 2006) 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 candidatesfor multiple diseases, e.g. malaria and cancer. 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 a fully operational and integrated drug discovery team, which is rare 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.

 My aim as Head of the DDU is to develop translational research at Dundee by integrating my and other’s experience of Drug Discovery in the Pharma/Biotech sector with academic life-sciences research. My role in leading a high quality, multi-disciplinary drug discovery team is to identify leads to validate novel drug discovery targets in animal models of disease and where appropriate develop them into new treatments.

I have overall responsibility for the Unit’s direction, strategy, scientific quality, delivery of outputs to milestones and building collaborations. Cross-DDU working groups, with input from key opinion leaders, ensures the DDU constantly improves its working practices and approaches, to make certain it is at the forefront of best practice for most effectively running drug discovery projects.

The Drug Discovery for Tropical Diseases Initiative was a programme to discover high quality drug candidates for neglected diseases. The initiative was initially funded by the Wellcome Trust, with a budget of £8.1m over five years. A second programme to work on kinetoplastid diseases, (African sleeping sickness, Leishmaniasis and Chagas disease) in collaboration with GlaxoSmithKline’s Kinetoplastid Diseases DPU, Tres Cantos, Spain, was funded by the Wellcome Trust in 2011 (£8.6m over 5 years).

In addition, we are funded by MMV to discover drug candidates for malaria, by the Foundation for NIH to discover leads for TB within the HIT-TB consortium and to carry out Lead Optimisation for Diseases of the Developing World within a programme supported jointly by the Bill and Melinda Gates Foundation and the Wellcome Trust.

Further, the DDU seeks to work in collaboration with groups identifying high impact, novel biology. Within the collaborations the DDU seeks to identify high quality compounds i) to enable the target originating group to develop their understanding of the biology, ii) to partially validate the potential drug target and iii) use them as start points for drug discovery programmes.

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. Two compounds which originated from the project are currently undergoing Phase II clinical trials in cancer patients.

My particular area of interest is in the design and use of fragment libraries to accelerate drug target validation and lead identification. In an era of restricted budgets, the use of high throughput screening to determine target druggability and identify lead compounds is not sustainable due to resource and cost issues. The use of fragment screening can cost effectively and efficiently carry out these functions at a fraction of the cost. The challenge is to develop methods and approaches which do not require structural information to develop the fragment hits. Dundee is seeking to work with multiple partners to develop new fragment libraries suitable for tackling difficult drug targets, e.g. protein-protein interactions. In particular we are seeking to increase the 3 dimensionality of the compounds in the library.

Publications

  1. From On-Target to Off-Target Activity: Identification and Optimisation of Trypanosoma brucei GSK3 Inhibitors and Their Characterisation as Anti-Trypanosoma brucei Drug Discovery Lead Molecules: A. Woodland, R. Grimaldi, T. Luksch, L.A.T. Cleghorn, K.K. Ojo, W.C. Van Voorhis, R. Brenk, J.A. Frearson, I.H. Gilbert and P.G. Wyatt ChemMedChem, 2013, 8(7), 1127-1137
  2. Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors, S. Brand, L.A.T. Cleghorn, S.P. McElroy, D.A. Robinson, V.C. Smith, I. Hallyburton, J.R. Harrison, N.R. Norcross, D. Spinks, T. Bayliss, S. Norval, L. Stojanovski, L.S. Torrie, J.A. Frearson, R. Brenk, A.H. Fairlamb, M.A.J. Ferguson, K.D. Read, P.G. Wyatt and I.H. Gilbert J. Med. Chem., 2012, 55(1), 140–152
  3. Design, Synthesis and Biological Evaluation of Trypanosoma brucei Trypanothione Synthetase Inhibitors, D. Spinks, L.S. Torrie, S. Thompson, J.R. Harrison, J.A. Frearson, K.D. Read, A.H. Fairlamb, P.G. Wyatt and I.H. Gilbert ChemMedChem 2011, 7(1), 95-106.
  4. Identification of Inhibitors of the Leishmania cdc2-Related Protein Kinase CRK3. L.A.T. Cleghorn, A. Woodland, I.T. Collie, L.S. Torrie, N. Norcross, T. Luksch, C. Mpamhanga, R.G. Walker, J.C. Mottram, R. Brenk, J.A. Frearson, I.H. Gilbert and P.G. Wyatt, ChemMedChem, 2011, 6(12), 2214-2224
  5. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness, J.A. Frearson, S. Brand, S.P. McElroy, L.A.T. Cleghorn, O. Smid, L. Stojanovski, H.P. Price, M.L.S. Guther, L.S. Torrie, D.A. Robinson, I. Hallyburton, C.P. Mpamhanga, J.A. Brannigan, A.J. Wilkinson, M. Hodgkinson, R. Hui, W. Qiu, O.G. Raimi, D.M.F. van Aalten, R. Brenk, I.H. Gilbert, K. D. Read, A.H. Fairlamb, M.A.J. Ferguson, D.F. Smith and P.G. Wyatt, Nature 2010, 464(7289), 728-732

 

Impact

Kinetoplastids

  • In collaboration with Prof Fairlamb (UoD) identified Fexinidazole as suitable for Phase II clinical trials for VL in Africa – Trials to be carried out by DNDi
  • Potential drugs for visceral leishmaniasis - 1 series in late lead optimisation in partnership with GSK
  • Potential drugs for Chagas disease – compound series with activity in an acute model of disease
  • African animal trypanosomiasis - Potential development candidates for treatment of animal trypanosomiasis - under development in partnership with GALVmed

Malaria

  • Potential pre-clinical development candidate for malaria - ongoing candidate selection activities with MMV

Tuberculosis

  • Multiple hit series identified from screening the DDU’s compound collection against TB growing in culture – ongoing collaboration within HIT-TB
  • Series identified with activity in an animal model of TB - ongoing in collaboration with major Pharma companies

Innovative Targets Portfolio

  • 2 Projects partnered with GSK’s Discovery Partnerships with Academia (DPAc)
  • Identified human NMT inhibitors as possible drug candidates for cancer - Partnership with a Canadian consortium
  • Tool compounds identified for multiple targets