One of the biggest challenges in the control and elimination of malaria is the emergence of drug-resistant strains of the most virulent causative agent Plasmodium falciparum. Therefore, new drugs for malaria with novel modes of action and activity across multiple stages of the parasite life-cycle are urgently needed to combat drug resistance and contribute to malaria elimination efforts.
The drug repositioning approach of using approved drugs as templates to generate derivatives optimized for a new disease that is different to the original indication is an attractive approach. Target deconvolution in the new disease indication then provides opportunities for target-guided medicinal chemistry approaches. Within this context human kinase inhibitors are attractive starting points for drug repositioning for malaria since they have been extensively investigated. On the other hand, Plasmodium kinases essential for parasite survival and expressed at multiple stages of the malaria parasite lifecycle have been identified.1 With knowledge of protein structures/binding site for human kinase inhibitors, human kinase focused libraries being available for screening, and evidence of clinical validation of Plasmodium phosphatidylinositol 4-kinase type III beta - PfPI4KIIIβ,2 anticancer kinase inhibitors present an attractive opportunity for malaria drug discovery through repositioning known anticancer human kinase inhibitors.
This lecture will describe profiling and mechanism of action studies of anticancer kinase inhibitors with activity against the human malaria parasite Plasmodium falciparum.
References:
[1] Arendse et al ACS Infect Dis. 2021; doi:10.1021/acsinfecdis.0c00724
[2] Paquet et al Sci. Transl. Med. 2017, 9, eaad9735,DOI: 10.1126/scitranslmed.aad9735.