Anticancer inhibitors of Plasmodium PI4K as potential antimalarial agents Shakela, Natalia 1 ; Arendse, Lauren 2,3 ; Woodland, John G. 1,2,3 ; Wicht, Kathryn J. 1,2,3 ; Chibale, Kelly 1,2,3 1 Department of Chemistry and 2 Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town; 3 South African Medical Research Council Drug Discovery and Development Research Unit, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa There is an urgent need to address the emergence of resistance to current frontline antimalarial treatments by identifying drugs with novel mechanisms of action. 1 VE-821 is a potent anticancer agent shown to competitively bind to the human malaria parasite Plasmodium falciparum phosphatidylinositol 4-kinase ( Pf PI4K). Objective This work focuses on repositioning VE-821, a potent anticancer agent for the treatment of malaria, using a medicinal chemistry approach. Analogues of VE-821 with the potential to inhibit Pf PI4K were designed and synthesized. These analogues were evaluated for their in vitro antiplasmodium activities against drug-susceptible (NF54) and -resistant (K1) strains of P. falciparum as well as inhibition of Pf PI4K in biochemical assays. Molecular docking simulations were carried out to evaluate the binding of these compounds to the Pf PI4K homology model and rationalise biological data. Additionally, the risk of off-target human ( Hs ) kinase inhibition was investigated. Biological data indicate that synthesised derivatives of VE-821 have moderate to excellent in vitro inhibition of P. falciparum growth. These data, alongside enzyme inhibition data and molecular docking simulations suggest that Pf PI4K is likely the primary target for this series. In addition, the neutral derivatives of VE-821 demonstrate poor solubility, whereas the basic and acidic analogues show good aqueous solubility and microsomal metabolic stability. From a representative data set, the series shows excellent selectivity against the Pf PI4K Hs orthologues: phosphatidylinositol 4-kinase IIIβ ( Hs PI4KIIIβ), mitogen-activated protein kinase 4 ( Hs MAP4K4) and misshapen/ nik-related kinase 1 ( Hs MINK1). The collective results can be exploited in the design of druglike compounds for the treatment of malaria. References 1. Wicht K. J., Mok S, Fidock D. A. Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria. Annu Rev Microbiol . 2020 Sep 8;74:431-454. doi: 10.1146/annurev-micro-020518-115546.
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