Screening a protein kinase inhibitor library against Plasmodium falciparum

Irene Hallyburton, Raffaella Grimaldi, Andrew Woodland, Beatriz Baragaña, Torsten Luksch, Daniel Spinks, Daniel James, Didier Leroy, David Waterson, Alan H. Fairlamb, Paul G. Wyatt, Ian H. Gilbert, Julie A. Frearson

Protein kinases have been shown to be key drug targets, especially in the area of oncology. It is of interest to explore the possibilities of protein kinases as a potential target class in Plasmodium spp., the causative agents of malaria. However, protein kinase biology in malaria is still being investigated. Therefore, rather than assaying against individual protein kinases, a library of 4731 compounds with protein kinase inhibitor-like scaffolds was screened against the causative parasite, Plasmodium falciparum. This approach is more holistic and considers the whole kinome, making it possible to identify compounds that inhibit more than one P. falciparum protein kinase, or indeed other malaria targets. As a result of this screen, 9 active compound series were identified; further validation was carried out on 4 of these series, with 3 being progressed into hits to lead chemistry. The detailed evaluation of one of these series is described. This screening approach proved to be an effective way to identify series for further optimisation against malaria. Compound optimisation was carried out in the absence of knowledge of the molecular target. Some of the series had to be halted for various reasons. Mode of action studies to find the molecular target may be useful when problems prevent further chemical optimisation. Progressible series were identified through phenotypic screening of a relatively small focused kinase scaffold chemical library.