Phosphatidylinositol (PI) are phospholipids that mediate signaling cascades in the cell by binding to effector proteins[2]. Phosphoinositides 4-kinases is a key membrane of the phosphoinositide family, which synthesize phosphatiddylinoditol 4-phosphate (PI4P). Humans have two type II PI4Ks (α and β) and two type III enzymes (α and β)[3].
PI4KIIIβ is critical for mediating viral replication of a number of RNA viruses through the generation of PI4P enriched viral replication platforms. These membranous webs enriched in PI4P play essential roles in spatially concentrating viral replication proteins, and are key in intracellular viral replication[4].
PI4KIIIbeta-IN-10 is a potent inhibitor of PI4KIIIβ with very minor off-target inhibitor of PI4KIIIβ related lipid kinases (IC50 of 3.6 nM). The most potent of these molecules (PI4KIIIbeta-IN-10；compound 10) was screened over a panel of nine related lipid kinases and was >200 fold selective for PI4KIIIβ across all enzymes tested. Two of the most potent and selective molecules (compound 9+10) were also the most effective antiviral compounds in a cellular model of Hepatitis C virus replication, with the best balance of antiviral potency and low cellular toxicity. PI4KIIIbeta-IN-10 shows weak inhibition of PI3KC2γ (IC50 ~1 µM), PI3Kα (~10 µM), and PI4KIIIα (~3 µM), and <20% inhibition at concentrations up to 20 µM for PI4K2α, PI4K2β, and PI3Kβ[5].
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