Origins of OSM Series 3
In 2010, GlaxoSmithKline (GSK) released chemical and biological data pertaining to some 13,500 compounds that displayed potent antimalarial activity in vitro (Nature paper). Medicinal chemists at the Medicines for Malaria Venture (MMV) identified several compounds present in this dataset which they believed to be excellent starting points, possessing low molecular weight, good projected solubility, high potency, low animal toxicity, no known intellectual property issues, clear ways to structural variation and, to the best of their knowledge, the compounds were not the subject of antimalarial research by any other group, and hence suitable for an open source project.
Series 3 is the third such series to be investigated and is based on an aminothienopyrimidine core.
The high throughput nature of the GSK screen carries the possibility of a false positive, and thus the first step was to produce more of the hit compound and confirm its antimalarial activity. This has been achieved, confirming the potency of the original hit. To see if the compound could be further optimized, the next step was be the synthesis of small sets of diverse analogs, as well as some exploration of the druggability (solubility, metabolic degradation etc) of the hit compound. If an interesting structure-activity relationship could be found, the compound might be suitable for lead optimization.
During 2013-2014 several analogs were synthesised, but all structural variation has resulted in dramatically decreased potency. Despite the promise of the hit, the project was parked. In 2019, the molecule was examined as part of the MALDA program, to try to determine its mechanism of action, leading to a significant amount of biological work led by Leann Tilley's lab in Melbourne validating that the MoA was via inhibition of Pfal Asn tRNA synthetase, and a paper has been submitted for publication on this work in mid-2023 (https://doi.org/10.21203/rs.3.rs-3198291/v1). These insights can help ongoing work in rationally improving OSM-S-106.