Final Report

1. Project objective

The objective of this project was to screen approximately 3,600 natural products of Eisai library against Leishmania donovani, Leishmania infantum and T. cruzi to identify new hit series that could be progressed and become new drug candidates for leishmaniasis and Chagas disease.

2. Project design

Eisai’s library (3,600 natural products collection) was screened against Leishmania donovani, Leishmania infantum and T. cruzi, followed by dose-response screens. Hit confirmation and hit profiling assays against Leishmania donovani, Leishmania infantum and Trypanosoma cruzi were conducted for the hits identified from the S2015-222 screening project, as well as from the S2013-121 screening project that was previously conducted using an Eisai compound library (chemical synthesis origin, a 20,000 compound collection). Screening of the additional analogues was conducted to more broadly search for active new scaffolds and strengthen the list of hit series, aiming to progress toward the hit-to-lead stage.

3. Results, lessons learned

A total of 3 new scaffolds (2 small series and 1 singleton) was confirmed to possess Leishmania activity from the data generated by the Swiss Tropical and Public Health Institute (STPH) and the Laboratory of Microbiology, Parasitology and Hygiene, the University of Antwerp (LMPH). A set of analogues related to those hits was sent to LMPH to assess our interest in these active scaffolds. After testing, one scaffold remained of potential interest based on a joint DNDi and Eisai hit analysis. A few additional analogues were screened at LMPH for this remaining one scaffold. The confirmed hit was, however, structurally similar to a chemical scaffold included in the DNDi NTD Drug Discovery Booster program. DNDi and Eisai jointly decided to discontinue follow-up efforts on this remaining hit series following a review of the data.

Lessons learned:

- In-depth preliminary discussion between Eisai and DNDi was needed to define more precisely the type of compounds to be selected for any new screens to be initiated, based on previous compound libraries screened to date by DNDi and the accumulated knowledge of the leishmania and Chagas discovery programs (e.g. deselection of known chemotypes, exclusion of CYP51 inhibition motives for Chagas disease, etc.)

- Need to expedite the hit confirmation process (DNDi responsibility)