Repurposing kinase inhibitor chemotypes as antimalarials

摘要

Abstract Malaria continues to be a leading cause of death in many countries and the emergence of drug resistance to artemisinin-based combination therapy, the last line of defence, poses a huge problem for malaria control. To halt the spread of drug resistance and contribute to malaria elimination, new therapies with different modes of action to drugs used clinically, and that are effective against multiple stages of the Plasmodium parasite life-cycle are urgently required. Plasmodium kinases, essential to both asexual blood stages of the parasite life-cycle responsible for disease symptoms and the sexual stages responsible for transmission of infection, have been identified as vulnerable targets for drug discovery. The success of human kinase inhibitors for the treatment of cancer and other human diseases has resulted in a large amount of chemical matter and biological data giving insight into kinase function, structure and selectivity, which can be harnessed for the development of kinase inhibitors against malaria. This project aims to identify a novel compound that is orally efficacious in an in vivo model of malaria infection by repurposing human kinase inhibitor chemotypes. This will include the optimization of two advanced compound series, originating from kinase-directed compound libraries, that display potent antiplasmodium activity. In addition, a phenotypic whole cell screen of a library of selective human kinase inhibitors will be carried out against Plasmodium falciparum asexual blood-stage parasites to identify additional chemotypes to enter hit-to-lead medicinal chemistry optimization. Complementary genetic and proteomic target-identification approaches will be carried out to identify the target/s of compounds with potent whole cell activity. In cases where assayable Plasmodium kinases are identified as the primary targets, hit-to-lead optimization will monitor both whole-cell and target activities, incorporating computer-aided drug design approaches to optimise for potency and selectivity relative to human kinase off-targets. Promising compounds based on antiplasmodium activity across multiple stages of the lifecycle, favorable drug metabolism and pharmacokinetic profiles and low toxicity, will be tested in a humanised mouse model of malaria infection. In addition to identifying a novel antimalarial drug, this research will set out to identify and chemically validate novel Plasmodium drug targets.