- Awarded Year2016
- Awarded Amount$549,447
- Development StageLead Identification
- Collaboration PartnersEisai Co., Ltd., SHIONOGI & CO., LTD., Takeda Pharmaceutical Company Limited, Drugs for Neglected Diseases initiative
Introduction and Background of the Project
This is a continuation project of 'Neglected Tropical Diseases Drug Discovery Booster' invested in 2014.
The NTD Drug Discovery Booster (Booster) project was launched in 2015 as an experiment aimed at speeding up the process and cutting the cost of finding new treatments for two diseases that put 350 million people at risk in 98 endemic countries affected with the Leishmania parasites and 100 million people at risk mainly in the Americas affected with the Trypanosoma cruzi parasites. The Booster Consortium led by DNDi entails exploring simultaneously high quality libraries to identify, in a speedy and effective way, hit series to optimize. The Consortium intends to continue the work of the Booster, feeding the mechanism with newly identified hit compounds from various hit finding exercises such as high throughput screening. The Consortium currently consists of three Japanese pharmaceutical partners (Eisai Co. Ltd, Shionogi & Co., Takeda Pharmaceutical Company Limited.) funded by GHIT Fund and AstraZeneca plc. and Celgene Corporation. Institut Pasteur Korea is also an important partner who is screening all the compounds.
The Booster II has the following two objectives;
Objective 1: Delivering novel chemical series for leishmaniasis & Chagas disease
The Booster II consortium will rapidly expand at least five promising hits/hit series against Leishmania donovani and T. cruzi, the causative agents of leishmaniasis and Chagas disease, respectively. This will provide series with well-developed structure activity relationships (SAR) ready for immediate in vivo proof of concept studies or, where necessary, focused medicinal chemistry optimization to provide improved tools ready for in vivo studies.
Objective 2: Complete lead evaluation from previous Booster project (Booster I)
Hit series previously identified by the Booster I (4-5 series) will complete their investigation towards in vivo proof of concept studies, leading to at least one series entering into lead optimization.
Over the next year, the Booster Consortium will run at least 10 iterations of the booster. A single booster iteration consists of a virtual screen (in silico) at each partner company, followed by experimental testing against parasite(s) of interest. The starting points for these iterations will come from two sources:
l At least five new seed compounds for L. donovani or T. cruzi (with 1-2 screening iterations each).
l Molecules identified as “improved hits” during previous iterations from the Booster I (e.g. continuation of the booster process from years 1 & 2)
Expected output is 1-2 hit series per parasite showing encouraging in vivo activity (inclusive of any historic hit series progressed into lead optimization from Booster I).
How can your partnership (project) address global health challenges?
The Booster consortium offers a more effective discovery approach to contribute to a potential successful new treatment for leishmaniasis or Chagas disease.
For visceral leishmaniasis, existing drugs produce variable efficacy and serious toxicities; only one is administered orally and the rest are given by painful intra-venous/intra-muscular injections. In addition, there is a dichotomy of efficacy in drug action in visceral leishmaniasis-endemic regions of the world. To date, the medical needs in visceral leishmaniasis are moderately to well-met in South Asia. However, in East Africa and Latin America the efficacy and tolerability of current visceral leishmaniasis therapies remain a challenging area for improvement. Ideally, what is needed in the treatment of visceral leishmaniasis is a simple oral combination therapy that would prove advantageous/effective in maintaining or improving efficacy, improving tolerability and preventing or delaying the emergence of resistance. Furthermore, a treatment adapted to field conditions, with shorter duration and which could be used pan-geographically, would be optimal.
In the case of Chagas disease there are even fewer treatment options than for visceral leishmaniasis. Monotherapy with nifurtimox or benznidazole (both from the same nitroheterocycle class) remain the only recognized treatments, but these require long treatment courses, produce variable efficacy, and cause serious side effects resulting in 20-30% discontinuations of treatment. Therefore, it is crucial that new classes of effective, well-tolerated, orally-acting and short-course treatments are progressed into the clinic to provide improved options for patients. New classes of drugs for Chagas disease are also essential to enable development of combination therapies to combat the risk of development of resistance to monotherapies.
What sort of innovation are you bringing in your project?
The Booster process benefits from simultaneously searching a combined compound collection of several million high-quality, drug-like, small molecules and rapidly testing them in the same, standardized in vitro assays to develop a robust SAR for the series. The Booster collection of compounds, which each pharmaceutical company has been collecting and preparing for its own drug discovery research, clearly offers a significant advantage. The combination of different scientific approaches to the in silico screening question results in a broader and more varied screening of compounds with potential parasitic activity compared to what may be synthesized in a traditional hit to lead project. The first 18 months of the Booster consortium have successfully validated the approach, demonstrating a clear advantage of the use of collaborative in silico screening across pharmaceutical partners. In particular, the ability of the booster process to identify new areas of chemical space via a first iteration and then provide an investigation of that chemical space via subsequent second (and third) iterations has led directly to the discovery of new hit series against both parasites of interest. The Consortium intends to continue the work of the Booster, feeding the Booster mechanism with newly identified hit compounds from various hit finding exercises such as high throughput screening resulting in new hit series for entry into future lead optimization programs.
Role and Responsibility of Each Partner
Takeda, Shionogi and Eisai will perform in silico screening of their internal libraries around each seed. They will prepare plates of compounds for shipment to the DNDi screening centre for testing. The companies will also provide intellectual input on the analysis of results coming from the iterations, as well as provide any additional relevant internal information about their compounds chosen for inclusion in a hit series.
DNDi will coordinate the project, conduct the experimental screening of the compounds via one of its dedicated screening centres, and complete the computational and medicinal chemistry analysis of the screening results.
Others (including references if necessary)
The results from the Booster consortium have been presented as a poster at the EFMC ISMC meeting (Manchester, UK, Aug 2016).