MAJOR INITIATIVES
The Dundee Drug Discovery Unit has two major remits, neglected tropical diseases and innovative targets and pathways. The DDU has received funding from a number of sources including: the Wellcome Trust, SRIF/UoD, Wolfson Foundation, DNDi (Drugs for Neglected Diseases Initiative), European Regional Development Fund, Scottish Funding Council, and SULSA.
Neglected Tropical Diseases
In the undeveloped world, over 350 million people are at risk from neglected diseases. Existing drugs to treat diseases such as African sleeping sickness, Chagas disease, Leishmaniasis, and Malaria are often expensive, difficult to administer, unsafe and increasingly ineffective due to development of resistance by the parasites that underpin these conditions.
The parasites which give rise to these neglected diseases are well understood, yet this knowledge has not been translated into modern therapeutics for such diseases. In fact, of all the new drugs to reach the market in the last 25 years, only 1% was for neglected disease. In response to this gap, we are working to develop both validated lead series and candidate drugs ready to enter formal preclinical development. This work has been primarily funded by the Wellcome Trust and more recently by DNDi (Drugs for Neglected Diseases Initiative).
Our goal is to develop compound series to a level where we can identify candidate molecules for entry into formal pre-clinical development, and to develop lead series that we can partner with other organizations through lead optimization.
These programmes in this area are managed within an overall portfolio of molecular target and phenotypic approaches to generate validated hits, leads and preclinical candidates. Importantly the DDU partners with DNDi for downstream clinical activity providing a clear mechanism by which leads and candidates produced by the DDU can reach patients.
We have progressed 18 targets and gene families, through both molecular target and phenotypic approaches, to hit compound identification. We currently have 5 active projects ongoing within this area, with our most advanced project ready for candidate selection studies for Stage 1 HAT and also undergoing lead optimisation for Stage 2 HAT. In conjunction with DNDi/Scynexis, we also have a second project in lead optimisation for Stage 2 HAT This area is supported by funding from several sources:
The Wellcome Trust (£8.1M from March 2006 to March 2011). Within this project we have focused primarily on human African trypanosomiasis. Our aim is to produce a candidate molecule for entry into formal preclinical development by March 2011.
Drugs for Neglected Diseases (£1.8M from April 2009 to March 2014). We are focusing primarily on developing lead compounds for visceral Leishmaniasis.
Medicines for Malaria Venture. We have carried out a small project with MMV to find hits with the potential to be developed as antimalarials.
Innovative Targets and Pathways
The DDU also has a strong commitment to facilitating the translation of fundamental research. Through the identification and development of lead compounds we aim to validate putative drug targets and investigate disease pathways. In this endeavour we do not seek to replicate the activities of the BioPharmaceutical sector but to complement them by addressing highly novel targets and pathways.
In this respect we are keen to address novel mechanisms and assess their druggability. For these novel targets, there is usually little precedence for drug discovery. Such projects are enabled through collaboration with research groups throughout the UK using a variety of funding bodies.
Currently we have more than 15 distinct projects within this portfolio of activity covering a range of therapeutic areas including oncology, anti-fungals, gram-negative anti-bacterials, anti-virals, atopic dermatitis and pain. Our goal in these projects is to develop them to an in vivo proof of concept stage (or lead series) and then to partner appropriately for further development. Thus we progress novel targets through hit discovery, hit validation and 'hits to lead' chemistry to establish proof of concept in vivo.
Stem Cell Technologies Programme
The DDU is also active in the exciting and rapidly progressing area of stem cells. In collaboration with ITI-Life Sciences and Cellartis (Medipark, Dundee) we are seeking to develop the in vitro drug discovery cell models of the future. This is being approached through the rational application of specific biology-directed small molecule compound sets to human embryonic stem cells in an automated high throughput screening environment. To date we have identified and validated multiple small molecule series which influence survival, propagation and pluripotency of human embryonic stem cells (hES) cells in culture. Our current efforts are directed at small molecules which support and/or drive directed differentiation along specific lineages.