references
R&D MODEL & PORTFOLIO
SCREENING
Screening for kinetoplastids (leishmaniasis, Chagas disease, human African trypanosomiasis)
OVERALL OBJECTIVE:
Establish a robust portfolio of drug discovery quality hits for the three kinetoplastid diseases, with a focus primarily on visceral leishmaniasis (VL) and Chagas disease
2015 OBJECTIVE: Focus high throughput
screening on identification of novel hit series for VL and Chagas disease by screening larger size compound libraries, exploring new “chemical space” and open source drug discovery initiatives
During 2015, over 300,000 compounds (representing more than 820,000 wells) were evaluated, with a focus on visceral leishmaniasis
in Chagas patients. A new in vitro protocol for T. cruzi amastigotes which can differentiate between CYP51 inhibitors (such as azoles and other scaffolds) and benznidazole by determining time kill and percentage kill profiles was developed in collaboration with Swiss TPH. This assay has been integrated into our discovery cascade and is routinely used to profile and prioritize nonCYP51 T. cruzi hits. Over 50 novel VL and Chagas active scaffolds were identified in 2015 from screening efforts. DND i has actively collaborated with MMV on the development of a “Pathogen Box”- a collection
Medium throughput screening for kinetoplastids – leishmaniasis, Chagas disease, and HAT (Trypanosoma brucei)
PARTNERS: The Swiss Tropical and Public
Health Institute (Swiss TPH), Switzerland; the Laboratory of Microbiology, Parasitology, and Hygiene (LMPH), University of Antwerp, Belgium; and the Walter Reed Army Institute of Research (WRAIR), USA
MAIN COMPOUND LIBRARIES: AbbVie, USA;
Anacor Pharmaceuticals Inc., USA; Astellas Pharma, Japan; AstraZeneca, UK; Celgene, USA; Daiichi Sankyo, Japan; Eisai Co. Ltd, Japan; GSK, Tres Cantos, Spain; Institut Pasteur Korea, South Korea; London School of Hygiene and Tropical Medicine (LSHTM), UK; Medicines for Malaria Venture (MMV), Switzerland; Merck, USA; Microbial Chemistry Research Foundation, Japan; Pfizer Ltd, UK; University of Dundee, UK; Sanofi, France; Takeda Pharmaceutical Company Ltd, Japan; TB Alliance, USA
Number of compounds screened
Screening for filarial diseases
OVERALL OBJECTIVE:
143,376
217,263
2013
170,000
300,000
2015
Identify new drug candidates using targeted compounds, primarily from repurposing libraries or focused sets with known antihelminthic activity from animal health companies
2015 OBJECTIVE: Identify 1-2 new
2012 2012 0
2014
of 400 drug-like compounds for multi-purpose screening – and has supplied a number of “hit” compounds for the kinetoplastids for consideration; seventy of these 400 compounds show activity against kinetoplastids. High throughput screening (large-size libraries) for leishmaniasis (Leishmania) and Chagas disease (Trypanosoma cruzi)
PARTNERS: The Institut Pasteur Korea,
candidates
and Chagas disease, in five DNDiPartner screening centres. This includes several chemical collections and sets of chemical analogues of hits/hit series from pharmaceutical and biotechnology companies. Commercial compound libraries from Axxam, Bioascent, and SPECS have been screened, together with TB Alliance’s “Active” and MMV’s “Biofocus” collections. Drug candidates which target the enzyme CYP51 are very common hits in T. cruzi screens. However, recent clinical studies with fosravuconazole and posaconazole have shown that this is not a valid drug target
South Korea, and the Drug Discovery Unit, University of Dundee, UK
