Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening

Here we report the discovery of a
selective inhibitor of Aurora
A, a key regulator of cell division and potential anticancer target.
We used the atom category extended ligand overlap score (xLOS), a
3D ligand-based virtual screening method recently developed in our
group, to select 437 shape and pharmacophore analogs of reference
kinase inhibitors. Biochemical screening uncovered two inhibitor series
with scaffolds unprecedented among kinase inhibitors. One of them
was successfully optimized by structure-based design to a potent Aurora
A inhibitor (IC50 = 2 nM) with very high kinome selectivity
for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation
and disrupts binding to its activator protein TPX2, which impairs
Aurora A localization at the mitotic spindle and induces cell division
defects. This phenotype can be rescued by inhibitor-resistant Aurora
A mutants. The inhibitor furthermore does not induce Aurora B specific
effects in cells.