Neglected Tropical Diseases Drug Discovery Booster
Project Completed

Introduction and Background of the Project

Early stage drug discovery can be an expensive and time-consuming process to find potential molecules to fight neglected diseases. Over the past decade, DNDi has invested heavily in identifying compounds active against Leishmania and T. cruzi – the causative agents of Leishmaniasis and Chagas disease respectively, and in accessing quality compound libraries to identify valuable hits for optimization as potential drugs to tackle these diseases. Despite such investment, identifying new chemical series that kill parasites such as Leishmania and T. cruzi has proven very difficult. Initially, DNDi accessed small, publicly available compound libraries and tested them in the low throughput assays available at the time. Through bilateral agreements with several pharmaceutical companies, and with the new screening assays developed by DNDi, larger collections of quality compounds were then screened in medium to high throughput assays. Success has been hindered nonetheless, most notably due to the difficulty in accessing large compound libraries of high quality and with sufficient diversity, which are critical in identifying valuable hits for optimization. The specific objective of the project is to deliver novel chemical series for leishmaniasis and Chagas disease - two diseases that put 350 million people risk in 98 endemic countries affected with the Leishmania parasites and 100 million people mainly in the Americas affected with the T. cruzi parasites.

How can your partnership (project) address global health challenges?

With GHIT Fund’s support and the three collaborating partners – Takeda, Shionogi and Eisai, the consortium aims at selecting molecules among the tens of millions of compounds each month and screening them against these deadly diseases. This new mechanism offers a more effective discovery approach. Called the Neglected Tropical Disease Drug Discovery Booster, the consortium led by DNDi will entail working with our three Japanese partners in a way that would simultaneously explore high quality libraries to identify, in a speedy and effective way hit series to optimize. The goal is to generate a clinical candidate in a fraction of the time generally required through traditional approaches. As compared to existing “pre-competitive” models of R&D, the innovation of the “NTD Booster” lies in companies accepting to share with DNDi, upfront, structural and functional information that is key to rapidly identify promising hit series. The collaborating partners will rapidly expand at least four promising hits /hit series each against the causative agents of these two diseases. This will provide series with well-developed structure activity relationship ready for immediate in vivo proof of concept studies or focused medicinal chemistry optimization to provide improved tools ready for in vivo studies.

What sort of innovation are you bringing in your project?

The NTD Drug Discovery Booster will overcome the hurdles and limitations related with current the R&D model. It will enable DNDi to further explore the extensive compound collections of our three collaborators, and also access the data linked to such libraries. The power of the approach relies on the unique possibility to combine the chemical information provided by each member to deliver hit series, and to avoid the lengthy and costly hit expansion process. The entire process will take approximately 3 to 4 months to go from initial in-silico screen to a series entering the lead optimization (LO) process. This compare with the 12 to 18 months generally needed to conduct the screening and the hit expansion leading to a possible candidate to optimize. The quality of hit series and the structure-activity-relationship produced thanks to the collective information gathered across the members will also greatly impact the speed of the LO, and significantly boost our ability to obtaining a clinical candidate. The best hit series will be described as a product of the collective effort of the members, and entered into DNDi’s lead optimization program. No individual member takes the sole credit of such output. The Best Hit Series and the optimized lead resulting from the LO program is made available to DNDi without restriction for all purposes related to the research, development, and implementation of drug products for the treatment of Leishmaniasis and Chagas disease. Thus, by accepting to share a very small amount of structural and functional information, the chances of pulling out the best possible hit series are dramatically increased, without significant risks for the members. On the contrary, all members will be acknowledged for any results coming out of the NTD Booster, and thus contribute to a potential successful new treatment for Leishmaniasis or Chagas disease.