Final Report

1. Project objective

The objective of the project is to identify novel antimalarial compounds from a 49,920 compound Daiichi Sankyo library. The hit compounds identified should meet MMV and GHIT criteria for antimalarial hit compounds and be suitable for progression to the hit to lead phase.

2. Project design

Daiichi Sankyo (Tokyo, Japan) supplied collaborators at Pivot Park Screening Center (Oss, Netherlands) with a library of 49,920 compounds for testing in a whole cell assay to measure growth inhibition of the asexual blood stage of the malaria parasite. The strains were tested in drug sensitive (PfNF54) and drug resistant (PfDd2) strains of the malaria parasite and for cytotoxicity (HepG2). Active compounds were prioritized using a Multi Parameter Optimization (MPO) scoring profile, structural novelty and ‘chemical attractiveness’. The top ranked compounds were re-synthesized and further profiling carried out (parasitology, ADME and safety) to confirm potential for further development.

3. Results, lessons learned

Daiichi-Sankyo provided a library of 49,920 compounds for testing in a whole cell phenotypic high throughput screen (HTS) for antimalarial activity using P. falciparum NF54 asexual blood stage parasites. The HTS was carried out at Pivot Park Screening Center. Following the single concentration HTS, Daiichi Sankyo selected 411 compounds (> 25% inhibition at 2 μM) for concentration response experiments (NF54 and Dd2) and measurement of cytotoxicity (HepG2). The compounds are structural distinct from actives identified in the previous MMV-DS GHIT funded Screening Platform project. Daiichi Sankyo and MMV prioritized 11 compounds for further profiling using a MMV StarDrop MPO scoring profile, structural novelty and ‘chemical attractiveness’. The MPO score is derived from the weighted importance of eight properties, including experimentally measured potency, selectivity over cytotoxicity in a mammalian cell line, alerts for undesirable substructures and various 'drug like' properties. The selected compounds were profiled in the assays described in the MMV Active Confirmation cascade to assess potency, mechanism of action, solubility and metabolic stability (PfN54, PfDd2, multiplex cross-resistance, HepG2, LogD, kinetic solubility, human liver microsomes and rat hepatocytes). The project team will review the data and series meeting MMV and GHIT criteria for further development will form the basis of a future GHIT HTLP.