Plasmodial Kinase Inhibitors: License to Cure?

Abstract

Advances in the genetics, function, and stage-specificity of Plasmodium kinases has driven robust efforts to identify targets for the design of antimalarial therapies. Reverse genomics following phenotypic screening against Plasmodia or related parasites has uncovered vulnerable kinase targets including PI4K, PKG, and GSK-3, an approach bolstered by access to human disease-directed kinase libraries. Alternatively, screening compound libraries against Plasmodium kinases has successfully led to inhibitors with antiplasmodial activity. As with other therapeutic areas, optimizing compound ADMET and PK properties in parallel with target inhibitory potency and whole cell activity becomes paramount toward advancing compounds as clinical candidates. These and other considerations will be discussed in the context of progress achieved toward deriving important, novel mode-of-action kinase-inhibiting antimalarial medicines.

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…Following on from the success of targeting of the plasmodial kinome, Chibale et al. screened the Pathogen Box identifying MMV024101 ( 474 ) as their hit compound .…”

Malaria and tuberculosis as diseases of neglected populations: state of the art in chemotherapy and advances in the search for new drugs

“…Researches for antituberculosis and antimalarial drugs from protein kinase inhibitors -Protein kinases play as key controllers of signal transduction, being responsible for regulating essential cellular processes, such as growth, development and replication. (117,118,119) Therefore, human kinases inhibitors have been extensively investigated as therapeutic agents for several diseases, as cancer, inflammatory, and cardiovascular illnesses. (119) There are large libraries of protein kinase inhibitors, which have been searched in designing of potential antimicrobial drugs against tuberculosis and malaria.…”

“…(117,118,119) Therefore, human kinases inhibitors have been extensively investigated as therapeutic agents for several diseases, as cancer, inflammatory, and cardiovascular illnesses. (119) There are large libraries of protein kinase inhibitors, which have been searched in designing of potential antimicrobial drugs against tuberculosis and malaria. However, the development of kinase inhibitors is still a major challenge, due to the lack of knowledge of the role of these proteins in infections.…”

Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites

“…They are also attractive drug targets for many infectious disease [24,25]. Given the success in developing drugs targeting human kinases, Plasmodium kinases are attractive targets and kinase inhibitors have been explored as a potential next generation of antimalarials [26]. Surprisingly, the tyrosine kinase family seems to be absent in the malaria parasite genome although a number of putative tyrosine kinase-like kinases (TKLs) have been found in Plasmodium species [24,27].…”