Development of Inhibitors for Phosphatidylinositol Kinases

The development of small-molecule inhibitors for two types of human phosphatidylinositol kinases (class III PI3-kinase and class III PI4-kinase) is described. The first part consists of an analysis of structural differences between class I PI3-kinase and class III PI3-kinase, followed by structure-guided synthesis of inhibitors exhibiting moderate specificity for class III PI3-kinase over class I PI3-kinase. The second part consists of combinatorial synthesis and assay-guided development of inhibitors for class III PI4-kinase alpha and beta, with the goal of producing compounds useful for the inhibition of HCV genotype 2a replication in hepatocytes with minimal toxicity. Several examples of compounds exhibiting varying selectivity for class III PI4-kinase over the evolutionarily related class I PI3-kinases and protein kinases are ultimately developed, including compounds which are effective at inhibiting HCV replication in hepatocytes at sub-micromolar concentrations