Selective inhibitors of Plasmodium falciparum glycogen synthase-3 (PfGSK-3): New antimalarial agents?

Plasmodium falciparum glycogen synthase kinase-3 (PfGSK-3) is one of the eukaryotic protein kinases that were identified as essential for the parasite causing malaria tropica. Although the physiological functions of PfGSK-3 are still unknown, it had been suggested as a putative target for novel antimalarial drugs. The high structural similarity of PfGSK-3 and its human orthologue HsGSK-3 makes the development of selective PfGSK-3 inhibitors a challenging task. Actually, established GSK-3 inhibitors are either unselective or are more potent for inhibition of the mammalian GSK-3. A high throughput screening campaign identified thieno[2,3-b]pyridines as a new class of PfGSK-3 inhibitors. Systematic variation of the substitution pattern at the parent scaffold led to compounds which selectively inhibited the plasmodial enzyme. These compounds also exhibited activity against erythrocyte stages of the parasites. A hypothetical explanation for the selectivity of the new antimalarial compounds was enunciated based on the results of docking a selective inhibitor into a PfGSK-3 homology model and by comparison of the results with an X-ray structure of HsGSK-3 co-crystallized with a similar but unselective compound. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.