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- RFP Year2016
- Awarded Amount$780,000
- DiseaseNTD (Chagas disease)
- Development StageLead Identification
- Collaboration PartnersDaiichi Sankyo, Inc., Drugs for Neglected Diseases initiative
- Past Project
Introduction and Background of the Project
Daiichi-Sankyo and DNDi jointly carried out a high throughput screening (HTS) of 40,000 compounds of the Pharamscape collection against Leishmania donovani and/or T. cruzi at Institut Pasteur Korea. A total of around 50 chemotypes were identified from primary active compounds followed in dose-response confirmation measurements. Three active chemotypes and 2 back-ups were prioritized in order to be progressed into Hit to Lead.
The objective of the project is to identify at least 1 -possibly 2 or more – progressable lead series meeting DNDi lead stage criteria for visceral leishmaniasis and/or Chagas disease
The design of the Pharmaspace collection and of the medicinal chemistry program associated with this Hit-to-Lead program has been made by Daiichi Sankyo. The design of the test cascade related to the biological (parasitology) assesssement of the active series selected for this project has been established by DNDi.
How can your partnership (project) address global health challenges?
Drug discovery and development at the early hit to lead stage for visceral leishmaniasis and Chagas disease is prone to a relatively high chance of failures. A critical mass of novel chemical series therefore needs to be identified and progressed through H2L and beyond in order to build up a solid portofolio of preclinical candidates aligned with the DNDi TPPs for those 2 kinetoplastid diseases.
What sort of innovation are you bringing in your project?
Daiichi Sankyo and DNDi have ensured through structure-based assessment that all active series included in this proposal do not have any overlap with past and current DNDi H2L/LO programs as well as scientific literature for VL and Chagas.
Role and Responsibility of Each Partner
Daiichi Sankyo will have the responsibility of the Design, synthesis of the compounds to be generate in the course of this project. Daiichi Sankyo will additionnaly be in charge of the assays related to the assessment of the physicochemical properties and DMPK of those compounds. The in vitro and in vivo parasitology assays (Leishmanial donovani and anti-T. cruzi) will be run at DNDi in collaboration with its mandated screening centers. Institut Pasteur Korea acting as the primary screening center in the frame of this Hit-to-Lead collaboration project.
1. Project objective
The objective of the project is to identify at least 1 - possibly 2 or more - progressable lead series meeting DNDi lead stage criteria for Visceral Leishmaniasis and/or Chagas Disease in line with DNDi published Target Product Profiles (TPPs) for new chemical entities.
2. Project design
Six chemotypes identified from the initial screening of the Daiichi-Sankyo 40,000 compound library were prioritized based on various perspectives to obtain progressable lead compounds. Medicinal chemistry efforts were carried out on three out of the six hit series. As soon as the most promising chemotype was determined, its ADME properties were investigated to obtain the pharmacokinetic (PK) parameters necessary for in vivo POC. Front-running compounds of the series were evaluated in vivo efficacy in a mouse acute model study. Various in vitro safety and pharmacology assays were also conducted to complete the profile of the series.
3. Results, lessons learned
Based on the results of in vitro ADMET profiling, mouse PK study, and mouse tolerability study of representative compounds, a phthalazine series has been prioritized and identified as a lead compound for further investigation. This series currently benefit from an outstanding nM range in vitro potency against Trypanosoma cruzi and is confirmed not to correlate with a CYP51 mechanism of inhibition within the series. A Proof of Concept efficacy study of the phthalazine series has demonstrated the in vivo efficacy of this series in a mouse assay model acutely infected with Trypanosoma cruzi, qualifying the phthalazine series as a promising lead series against Chagas disease in respect to the criteria defined by DNDi for lead optimization stage development. While specific properties of this phthalazine series still remain to be further optimized, chemical derivatization on the series clearly indicated that essential biological parameters (including in vitro Trypanosoma cruzi activity, selectivity, and CYP inhibition) as well as key physicochemical properties (such as solubility, permeability, log D) can be tuned via modification of the various regions of the molecules. The project therefore initiated the lead optimization effort in April 2020 with the renewed support from GHIT Fund. Lead compounds meeting criteria for Leishmania donovani could not be obtained in this research project.