2020 marks the five-year anniversary of the launch of the NTD Drug Discovery Booster (‘Booster’), a global consortium of pharmaceutical companies collaborating to identify new potential treatments for neglected tropical diseases. The Booster has focused primarily on leishmaniasis and Chagas disease, with activities supported by the Japanese Global Health Innovative Technology (GHIT) Fund.
In April 2015, the first chemical structure of interest to the Drugs for Neglected Diseases initiative (DNDi), ‘Seed Series 01’ (Seed S01), was communicated to the original four Booster partners, AstraZeneca, Eisai, Shionogi, and Takeda Pharmaceutical Company Limited. S01 had been shown to have potential to treat both leishmania and trypanosoma cruzi infections; however, the chemical structure required tweaking and optimization for it to meet the demanding criteria to progress as a drug candidate.
Over the weeks that followed, the vast proprietary chemical catalogues of our partner companies in the Booster were rigorously mined, using state-of-the-art algorithms to pull out examples of similar molecules to Seed S01, with the hope that some of them would demonstrate the sought-after improvements when tested against parasites.
By June 2015, hundreds of samples of these compounds started arriving at the lab of DNDi partner Institut Pasteur Korea, where they were evaluated for their impact against leishmania donovani and trypanosoma cruzi parasites. For the majority of these novel molecules, this was the first time they had ever been disclosed and shared outside of their owners’ research labs.
Three months later, in a previously unprecedented display of pre-competitive collaboration, the results from this effort were being shared openly amongst the partners. A second round of compound mining began, again yielding hundreds of new novel compounds for testing against the parasites.
By April 2016, a prioritized set of around 50 molecules from these efforts, drawn from all partners and shown to be similar variants to the original S01 seed, were approved to be handed to DNDi for further optimization – the so-called ‘S01 Hit Series’. These optimization efforts eventually led to identification of an advanced compound which could significantly reduce parasite burden in a T. cruzi infected mouse model.
In the five years since that first S01 communication, 22 new seeds have been analyzed by the Booster partners in much the same way. The initial four partners grew to eight, with Celgene (now part of Bristol-Myers Squibb), Merck, AbbVie, and Astellas joining forces with the original partners. Samples of over 18,000 compounds, often novel and proprietary to the Booster partners, have been shared openly with DNDi and in some cases amongst the partners. 12 of the 22 seeds profiled have led to new promising S01 Hit Series, and we now have four compounds coming from the Booster partners which are effective in animal models of kinetoplastid infection. The S07 seed has led to a series currently in the late stages of lead optimization and could deliver a pre-clinical candidate by 2021, and we expect further lead optimization programmes to be delivered in the near future.
The NTD Drug Discovery Booster in numbers
- 8 partners
- 22 seeds investigated
- 45 virtual screening iterations performed
- 18,000 compounds screened
- 13 hit series identified
- 12 compounds progressed to animal models of infection
- 4 compounds successful in animal models of infection
- 1 series progressed to lead optimization
Photo credit: Vinicius Berger-DNDi