Research

 

 

 

 

Screening

Screening for kinetoplastids (leishmaniasis, Chagas disease, human African trypanosomiasis)

  • Partners (since project start): AbbVie, USA; Anacor, USA; Astellas, Japan; AstraZeneca, Sweden; Bayer, Germany; Bioascent, UK; Bristol-Myers Squibb, USA; Celgene, USA; Centro National de Pesquisa em Energia e Materiais (CNPEM) LN Bio, Brazil; Drug Discovery Unit (DDU) at the University of Dundee, UK; E.I. du Pont de Nemours, USA; Eisai Co. Ltd, Japan; GlaxoSmithKline, Tres Cantos, Spain; Institut Pasteur Korea (IPK), South Korea; Johnson & Johnson, USA; Laboratory of Microbiology, Parasitology, and Hygiene (LMPH), University of Antwerp, Belgium; London School of Hygiene & Tropical Medicine (LSHTM), UK; Medicines for Malaria Venture (MMV), Switzerland; Merck (MSD), USA; Microbial Chemistry Research Foundation, Japan; Northwick Park Institute for Medical Research, UK; Pfizer, USA; Pfizer Animal Health, USA; Sanofi, France; Sanofi Merial, USA; Special Programme for Research and Training in Tropical Diseases (WHO-TDR); Takeda, Japan; TB Alliance, USA; Swiss Tropical and Public Health Institute (Swiss TPH), Switzerland; Shionogi & Co. Ltd, Japan; Sequella Inc, USA; University of Cape Town (UCT), South Africa.
  • Funding (since project start): Bill & Melinda Gates Foundation, USA; Department for International Development (DFID), UK; Dutch Ministry of Foreign Affairs (DGIS), the Netherlands; Federal Ministry of Education and Research (BMBF through KfW), Germany; GIZ on behalf of the Government of the Federal Republic of Germany, Germany; Global Health Innovative Technology (GHIT) Fund, Japan; Médecins Sans Frontières/Doctors without Borders, International; Ministry of Foreign and European Affairs (MAEE), France; Spanish Agency for International Development Cooperation (AECID), Spain; Swiss Agency for Development and Cooperation (SDC), Switzerland.

 

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

High-throughput screening (HTS) of core diversity libraries from several pharmaceutical companies (Sanofi, Takeda, Eisai, Merck, AbbVie) was completed against Leishmania donovani and Trypanosoma cruzi in 2014, in collaboration with screening partners (University of Dundee and Institut Pasteur Korea). Several new starting points are currently being followed up in hit profiling, annotation, and hit-to-lead programmes. A high-throughput screening assay which uses cidal axenic L. donovani was previously developed by the University of Dundee and is now part of DNDi’s routine VL screening cascade there, enabling the screening of very large collections (more than 50,000 compounds).

Several VL active series were identified from GlaxoSmith-Kline’s global compound library screen and progressed through a hit-to-lead programme by DNDi during 2014 in collaboration with the University of Dundee. Furthermore, a screening collaboration agreement with the university signed in December 2014 aims to screen approximately 500,000 compounds against VL.

 

Screening of repurposing libraries for filarial diseases

  • Partners (since project start): Northwick Park Institute for Medical Research, UK; University Hospital of Bonn, Germany; AbbVie, USA; Sanofi Merial, USA; GlaxoSmithKline, UK; Novartis AH, Switzerland; Johnson & Johnson, USA; National Museum of Natural History Paris (MNHN), France; Medicines for Malaria Venture, Switzerland; National Institute of Health, USA; Merck Sharp & Dohme, USA.
  • Funding (since project start): Bill & Melinda Gates Foundation, USA; Federal Ministry of Education and Research (BMBF through KfW), Germany; Brian Mercer Charitable Trust, UK.

 

  • Overall Objective: Identify new drug candidates using targeted compounds, primarily from repurposing libraries or focused sets with known antihelminthic activity from animal health companies.

With the limited throughput of phenotypic screening against filarial nematodes, screening large chemical libraries is not possible and DNDi has negotiated access to smaller focused chemical series that are more likely to give rise to drug candidates. These include indications sets (compounds that have progressed to pre-clinical or clinical research but failed to reach the market), well-annotated sets of compounds (e.g. bioavailable sets or compounds which have been through lead optimization), chemical series from veterinary anti-infective research programs, or orthologous sets (compounds directed against human targets with similar gene sequences to the parasites). Over 7,000 compounds were screened in vitro (Onchocerca) and in vivo (Litmosoides model) in 2014, including from bioavailability sets (such as AbbVie, GlaxoSmithKline, Sanofi), and other libraries with specific properties or indications (for example NIH, MMV): approximately 100 compounds have shown activity. Those with appropriate pharmacokinetic profiles are being screened in rodent models of onchocerciasis and lymphatic filariasis. Drug repurposing is high risk, but with the potential to be highly rewarding if successful; and although most compounds will probably not be suitable as macrofilaricidal drugs, they will be a rich resource for developing new clinical candidates.

In addition to compounds that kill the adult worm, DNDi is also investigating compounds that target the endosymbiotic Wolbachia bacterium. A number of promising drug candidates for both targets are under review.

 

NTD Drug Discovery Booster

In parallel to its ongoing bilateral collaborations for screening and lead optimization, in 2015 DNDi launched the NTD Drug Discovery Booster with several major pharmaceutical companies.

Overall Objective: Identify promising new compounds for treatment of leishmaniasis and Chagas disease by using a multilateral, simultaneous search process across several global pharmaceutical companies. The booster allows DNDi to access millions of unique compounds, generated over many decades of research, to screen for potential treatments or cures for these diseases.

Partners (since project start): AstraZeneca, UK; Celgene, USA; Eisai, Japan; Shionogi, Japan; Takeda Pharmaceutical Company Ltd, Japan.

 

Lead Optimization

  • Partners (since project start): AbbVie, USA; Anacor Pharmaceuticals Inc., USA; AstraZeneca, UK; Brazilian Biosciences National Laboratory, Brazil; Celgene, USA; Centre for Drug Candidate Optimization, Monash University, Australia; Epichem, Australia; Eskitis Institute for Cell and Molecular Therapies, Griffith University, Australia; Fundaçao de Apoio Universidade Federale de Sao Paolo, USP São Carlos, Brazil; GlaxoSmithKline, Tres Cantos, Spain; iThemba LABS, South Africa; Laboratory of Microbiology, Parasitology and Hygiene, Antwerp University, Belgium; London School of Hygiene and Tropical Medicine, UK; Merck, USA; Novartis Institute for Tropical Diseases, Singapore; Pfizer Ltd, UK; Sanofi, France; SCYNEXIS Inc., USA; TB Alliance, USA; TCG Life Sciences, India; Sandexis, UK; Universidade Estadual de Campinas, Brazil; University of Auckland, New Zealand; WuXi AppTec, China.
  • Funding (since project start): Bill & Melinda Gates Foundation, USA; Brazilian Development Bank (BNDES), Brazil; Department for International Development (DFID), UK; Dutch Ministry of Foreign Affairs (DGIS), the Netherlands; Federal Ministry of Education and Research (BMBF through KfW), Germany; FIOCRUZ, Brazil; GIZ on behalf of the Government of the Federal Republic of Germany, Germany; Global Health Innovative Technology (GHIT) Fund, Japan; Médecins Sans Frontières/Doctors without Borders, International; Ministry of Foreign and European Affairs (MAEE), France; Ministry of Health, Brazil; Spanish Agency for International Development Cooperation (AECID), Spain; Swiss Agency for Development and Cooperation (SDC), Switzerland; Other private foundations and individuals.

 

  • Overall Objective: Establish a robust portfolio of drug discovery quality lead series for the three kinetoplastid diseases.

With new chemical entities currently undergoing clinical development for human African trypanosomiasis (HAT), since 2012 the focus of screening and lead optimization efforts has been on identifying compounds to develop for VL and Chagas disease.

Many advances have been made during 2014. The first in vivo proof of concept for a new chemical class (VL series 12 – aminopyrazoles) from Pfizer was achieved in the early curative model of VL. A full lead optimization programme is now underway. Several compounds demonstrated excellent activity in vivo. Two advanced lead oxaboroles, DNDi-2166148 and DNDi-2310789, were identified and will be scaled up to enable exploratory toxicology studies, which could enable selection of one as an optimized lead for VL.

A programme is ongoing to identify nitroimidazole backups since VL-2098 did not successfully complete pre-clinical testing. Over 200 analogues have been prepared so far, and two backup compounds originating from different core structures have been selected and are being further profiled for in vivo efficacy and safety. Multiple hits from screening with several pharmaceutical partners or from other sources were progressed into hit confirmation and expansion studies. Several series have moved into the hit-to-lead stage for both Chagas disease and VL.

A number of pharmacokinetic and pharmacodynamic studies have been conducted in animal models of VL using existing and experimental drugs to build improved PK/PD models and ameliorate the translation of new drugs from discovery into clinical studies. In addition, a new screening cascade for Chagas disease has been implemented: the insight gained into the PK/PD relationship of compounds from additional in vitro assays coupled with a new in vivo model will enable compounds to be moved forward with more confidence.

Last update: October 2015