Phosphatidylinositol 4-kinases (PI4K) are enzymes responsible for the production of phosphatidylinositol 4-phosphates, important intermediates in several cell signaling pathways. PI4KIIα is the most abundant membrane-associated kinase in mammalian cells and is involved in a variety of essential cellular functions[3]. Phosphatidylinositol 4-kinases (PI4Ks) and small guanosine triphosphatases (GTPases) are essential for processes that require expansion and remodeling of phosphatidylinositol 4-phosphate (PI4P)-containing membranes, including cytokinesis, intracellular development of malarial pathogens, and replication of a wide range of RNA viruses[4]. KDU691, an imidazopyrazine with potent anti-parasitic activity against blood stage schizonts, gametocytes and liver stages, is a Plasmodium PI4K inhibitor. KDU691 selectively inhibits dihydroartemisinin-pretreated Plasmodium falciparum ring-stage parasites (IC50=1.5nM)[5]. KDU691 is selective for P. vivax PI4K over recombinant human PI4KβIII and PI3Kα, -β, -ɣ, and -δ (IC50s = 7.9, 8.8, 2.4, 8, and 3.4 µM, respectively), as well as VPS34 (IC50 = >9.7 µM) and 36 additional kinases in a panel of lipid and protein kinases (IC50s = >10 µM)[6]. During the 5 days of dosing, the animals that are treated with KDU691 show a transient yellow skin color since the fourth day. The KDU691 radical-cure group (group 691-RC) becomes blood-stage positive again at 31.8 days p.i. (range, 31 to 32 days). Clinical chemistry analysis of the group 691-RC monkeys reveals that bilirubin levels accumulate during the 5-day radical-cure treatment with KDU691[7].
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