Identification of Novel Aurora Kinase A (AURKA) Inhibitors via Hierarchical Ligand-Based Virtual Screening

Aurora kinases are essential for cell mitosis, amplified, and overexpressed in various human malignancies. Therefore, Aurora kinases have been promising targets for anticancer therapies, which has prompted an intensive search for their small-molecule inhibitors. In this work, we performed a hierarchical and time-efficient virtual screening cascade for scaffold hopping, aiming to obtain structurally novel and highly potent hit compounds targeting Aurora kinases. The cascade consisted of a shape- and an electrostatic-based protocol, combined with a QSAR-based selection protocol. This virtual screening cascade was used to screen two databases, one commercial database named the J&K database containing about 5.2 million diverse molecules and the Drugbank database. Experimental validations led to the identification of one structurally novel and highly potent hit compound (hit 1, found to possess an IC₅₀ of 8.1 and 19 nM for Aurora kinases A and B, respectively), which can be a promising starting point for further exploration. Additionally, Aurora kinases were identified as off-targets for hits 2-6 (Crizotinib, CI-1033, Dasatinib, Bosutinib, MLN-518), which are approved or investigational drugs as listed in Drugbank, plausibly suggesting targeting Aurora kinases may even contribute to their mechanism of action.