The replication of multiple enteroviruses including poliovirus, human rhinovirus, and coxsackievirus has been shown to require a myriad of host cellular factors for replication including phosphatidylinositol 4-kinase III beta (PI4KIIIβ). Since PI4KIIIβ is a crucial host factor for many viruses, PI4KIIIβ is an attractive drug target with a potential for multiviral therapeutic indications. We solved the structure of small moluclue inhibitors bound to PI4KIIIβ by X-ray crystallography. Leveraging of this structural information enabled the design of inhibitors that were highly potent for PI4KIIIb and highly selective over other lipid and protein kinases. Three scaffolds of ATP competitive reversible inhibitors were investigated for biochemical and antiviral potency, kinase selectivity, antiviral efficacy, and safety<i> in vivo</i>. The medicinal chemistry lead optimization of the developed compounds will be presented.

Chemical optimization of novel inhibitor classes selectively targeting PI4KIIIbeta: A host lipid kinase crucial for enterovirus replication

249th National Meeting (2015)

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