Lauren B Arendse, Susan Wyllie, Kelly Chibale, Ian H Gilbert.
ACS Infect Dis. 2021 Mar 12;7(3):518-534. doi: 10.1021/acsinfecdis.0c00724. Epub 2021 Feb 16. PMID: 33590753
Abstract
Protein and phosphoinositide kinases have been successfully exploited as drug targets in various disease areas, principally in oncology. In malaria, several protein kinases are under investigation as potential drug targets, and an inhibitor of Plasmodium phosphatidylinositol 4-kinase type III beta (PI4KIIIβ) is currently in phase 2 clinical studies. In this Perspective, we review the potential of kinases as drug targets for the treatment of malaria. Kinases are known to be readily druggable, and many are essential for parasite survival. A key challenge in the design of Plasmodium kinase inhibitors is obtaining selectivity over the corresponding human orthologue(s) and other human kinases due to the highly conserved nature of the shared ATP binding site. Notwithstanding this, there are some notable differences between the Plasmodium and human kinome that may be exploitable. There is also the potential for designed polypharmacology, where several Plasmodium kinases are inhibited by the same drug. Prior to starting the drug discovery process, it is important to carefully assess potential kinase targets to ensure that the inhibition of the desired kinase will kill the parasites in the required life-cycle stages with a sufficiently fast rate of kill. Here, we highlight key target attributes and experimental approaches to consider and summarize the progress that has been made targeting Plasmodium PI4KIIIβ, cGMP-dependent protein kinase, and cyclin-dependent-like kinase 3.