Final Report

1. Project objective

The objective of the project was to identify novel antimalarial compounds from approximately 20,000 compound Astellas 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

Astellas (Tokyo, Japan) supplied collaborators at Griffith University (Melbourne, Australia) with　a library of 20,000 compounds for testing in a whole cell assay to measure growth inhibition of the asexual stage of the malaria parasite. The strains were tested in drug sensitive (Pf3D7) and drug resistant (PfDd2) strains of the malaria parasite and for potential cytotoxicity (HEK293). Active compounds were prioritized and then the top ranked compounds were re-synthesized and further hit profiling carried out (parasitology, ADME and safety) to confirm potential for further development.

3. Results, lessons learned

20,000 compounds supplied by Astellas were tested against in a high-throughput 384-well asexual blood stage anti-malarial imaging assay. 407 active compounds were identified and re-tested (concentration-response) against drug sensitive (Pf3D7) and drug-resistant (PfDd2) strains of Plasmodium falciparum and for cytotoxicity in HEK293 cells. 27 compounds were identified with equal potency against Pf3D7 and PfDd2 < 1 μM and selectivity for the parasites (SI > 50). 10 compounds were selected for hit profiling and re-synthesis was initiated. The re-synthesis of 5 compounds was completed. The compounds were tested for their rate of parasite kill, hit deconvolution, DMPK and safety (HepG2 and hERG). The initial data obtained indicates that the compounds meet MMV and GHIT hit criteria with potential as acceptable starting points for a hit to lead project. Most compound have acceptable potency (Pf3D7 IC50 < 1 µM) and good solubility (KS > 100 µM) with scope to improve DMPK. Several of the compounds are inhibitors of the cardiac K+ (hERG) ion channel (EC50 < 1 µM). This is of concern and the molecules contain structural features likely to be associated with hERG binding. However, structural modification to reduce hERG binding is possible. The project team are currently reviewing the data and will decide if 2-3 compound series are suitable for a GHIT HTLP proposal.