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Awarded Amount$150,000DiseaseNTD (Chagas disease / Leishmaniasis)InterventionDrugDevelopment StageHit IdentificationCollaboration PartnersMitsubishi Tanabe Pharma Corporation , Drugs for Neglected Diseases initiative
1. Project objective
The objective of this project is to screen Mitsubishi Tanabe’s diverse collection of 51,200 molecules to discover compounds that kill Leishmania donovani and T. cruzi, the parasites that cause visceral leishmaniasis and Chagas disease. DNDi and Mitsubishi Tanabe will identify several progressable hit series which can meet GHIT and DNDi hit criteria.
2. Project design
The screening of the compounds was conducted by DNDi’s partner, Institut Pasteur Korea. The dose-response measurements focused on the compounds meeting lead-like criteria in association with a number of closely related non-hit analogues. A multi-parametric assessment was conducted by DNDi and Mitsubishi Tanabe to prioritize hit series.
3. Results, lessons learned
A total of 14 actives series were obtained out of Mitsubishi Tanabe’s diverse collection of 51,200 compounds. Three series are dually active against Leishmania donovani and T. cruzi while all other series are uniquely active against T. cruzi.
Those active series were reviewed by DNDi and Mitsubishi Tanabe in terms of novelty, potential for full cidality, selectivity against mammalian cell lines and SAR analysis. Nine active series were prioritized including three most promising series. Hit profiling of 33 representatives from those series in ADMET assays including chromatographic logD determination, solubility, permeability, metabolic stability in mouse liver microsome was completed. Activity profiling in panel of Leishmania donovani and T. cruzi assays and CYP51 inhibition was also carried out.
Those promising Leishmania and T. cruzi active series are novel to DNDi discovery programs and satisfy all criteria set by the GHIT Fund and DNDi, resulting in successful progression into Hit-to-Lead stage.